Lactone compounds for treating patient with precancerous lesions

ABSTRACT

Substituted lactone compounds are useful in the treatment of precancerous lesions and neoplasms.

RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.08/265,396 filed on Aug. 3, 1994.

TECHNICAL FIELD

This invention relates to compounds and methods for treatment orprevention of precancerous lesions.

BACKGROUND OF THE INVENTION

Each year in the United States alone, untold numbers of people developprecancerous lesions. These lesions exhibit a strong tendency to developinto malignant tumors, or cancer. Such lesions include lesions of thebreast (that can develop into breast cancer), lesions of the skin (thatcan develop into malignant melanoma or basal cell carcinoma), colonicadenomatous polyps (that can develop into colon cancer), and other suchneoplasms. Compounds which prevent or induce the remission of existingprecancerous or cancerous lesions or carcinomas would greatly reduceillness and death from cancer.

Approximately 60,000 people die from colon cancer, and over 150,000 newcases of colon cancer are diagnosed each year. For the Americanpopulation as a whole, individuals have a six percent lifetime risk ofdeveloping colon cancer, making it the second most prevalent form ofcancer in the country. Colon cancer is also prevalent in Western Europe.It is believed that increased dietary fat consumption is increasing therisk of colon cancer in Japan.

In addition, the incidence of colon cancer reportedly increases withage, particularly after the age of 40. Since the mean ages ofpopulations in America and Western Europe are increasing, the prevalenceof colorectal cancer should increase in the future.

To date, little progress has been made in the prevention and treatmentof colorectal cancer, as reflected by the lack of change in thefive-year survival rate over the last few decades. The only cure forthis cancer is surgery at an extremely early stage. Unfortunately, mostof these cancers are discovered too late for surgical cure. In manycases, the patient does not experience symptoms until the cancer hasprogressed to a malignant stage.

In view of these grim statistics, efforts in recent years haveconcentrated on colon cancer prevention. Colon cancer usually arisesfrom pre-existing benign neoplastic growths known as polyps. Preventionefforts have emphasized the identification and removal of colonicpolyps. Polyps are identified by x-ray and/or colonoscopy, and usuallyremoved by devices associated with the colonoscope. The increased use ofcolon x-rays and colonoscopies in recent years has detected clinicallysignificant precancerous polyps in four to six times the number ofindividuals per year that acquire colon cancer. During the past fiveyears alone, an estimated 3.5 to 5.5 million people in the United Stateshave been diagnosed with adenomatous colonic polyps, and it is estimatedthat many more people have or are susceptible to developing thiscondition, but are as yet undiagnosed. In fact, there are estimates that10-12 percent of people over the age of 40 will form clinicallysignificant adenomatous polyps.

Removal of polyps has been accomplished either with surgery orfiber-optic endoscopic polypectomy--procedures that are uncomfortable,costly (the cost of a single polypectomy ranges between $1,000 and$1,500 for endoscopic treatment and more for surgery), and involve asmall but significant risk of colon perforation. Overall, about $2.5billion is spent annually in the United States in colon cancer treatmentand prevention.

As indicated above, each polyp carries with it a chance that it willdevelop into a cancer. The likelihood of cancer is diminished if a polypis removed. However, many of these patients demonstrate a propensity fordeveloping additional polyps in the future. They must, therefore, bemonitored periodically for the rest of their lives for polypreoccurrence.

In most cases (i.e. the cases of so-called common sporadic polyps),polyp removal will be effective to reduce the risk of cancer. In a smallpercentage of cases (i.e. the cases of the so-called polyposissyndromes), removal of all or part of the colon is indicated. Thedifference between common sporadic polyps and polyposis syndromes isdramatic. Common sporadic polyp cases are characterized by relativelyfew polyps, each of which can usually be removed leaving the colonintact. By contrast, polyposis syndrome cases can be characterized bymany (e.g. hundreds or more) of polyps--literally covering the colon insome cases--making safe removal of the polyps impossible short ofsurgical removal of the colon.

Because each polyp carriers with it the palpable risk of cancerousdevelopment, polyposis syndrome patients invariably develop cancer ifleft untreated. Surgical removal of the colon is the conventionaltreatment. Many of these patients have undergone a severe change inlifestyle as a result of the disfiguring surgery. Patients have strictdietary restrictions, and many must wear ostomy appliances to collecttheir intestinal wastes.

The search for drugs useful for treating and preventing cancer isintensive. Indeed, much of the focus of cancer research today is on theprevention of cancer because therapy is often not effective and hassevere side effects. Cancer prevention is important for recovered cancerpatients who retain a risk of cancer reoccurrence. Also, cancerprevention is important for people who have not yet had cancer, but havehereditary factors that place them at risk of developing cancer. Withthe development of new genetic screening technologies, it is easier toidentify those with high risk genetic factors, such as the potential forpolyposis syndrome, who would greatly benefit from chemopreventivedrugs. Therefore, finding such anti-cancer drugs that can be used forprolonged preventive use is of vital interest to many people.

One way to find such drugs is to screen thousands of compounds for thesame biological activity found in known chemopreventive andchemotherapeutic drugs. Unfortunately, most chemotherapeutic drugs haveserious side effects that prohibit their long term use, or use inotherwise healthy individuals with precancerous lesions. These sideeffects, which are a result of the high levels of cyto-toxicity of thedrugs, include hair loss, weight loss, vomiting and bone marrow immunesuppression. Therefore, there is a need to identify new drug candidatesfor therapy that do not have such serious side effects in humans.

Recently, several non-steroidal anti-inflammatory drugs ("NSAIDs"),originally developed to treat arthritis, have shown effectiveness ininhibiting and eliminating the polyps. Polyps virtually disappear whenthe patient take the drug, particularly when the NSAID sulindac isadministered. However, the prophylactic use of currently availableNSAIDs, even in polyposis syndrome patients, is marked by severe sidereactions that include gastrointestinal irritations and ulcerations.Once NSAID treatment is terminated due to such complications, the polypsreturn, particularly in polyposis syndrome patients.

Sulindac has been particularly well received among the NSAIDs for thepolyp treatment. Sulindac is a sulfoxide compound that itself isbelieved to be inactive an anti-arthritic agent. The sulfoxide isreported to be converted by liver enzymes to the corresponding sulfide,which is acknowledged to be the active moiety as a prostaglandininhibitor. The sulfide, however, is associated with the side effects ofconventional NSAIDs. The sulfoxide is also known to be metabolized tosulfone compound, which is regarded to be inactive as an inhibitor ofprostaglandin synthesis.

SUMMARY OF THE INVENTION

This invention includes compounds and a method of treating patients withprecancerous lesions by administering a physiologically effective amountof those compounds described below to a patient in need of suchtreatment. Such compositions are effective in eliminating and inhibitingthe growth of precancerous lesions and neoplasms, but are notcharacterized by the severe side reactions of conventional NSAIDs.

The compounds used in the treatment of this invention are believed to beeffective on precancerous lesions either because they are activethemselves or because they are metabolized to active derivatives.

It was unexpectedly discovered that while the compounds of thisinvention do not greatly inhibit prostaglandin synthesis--prostaglandinsynthesis inhibition being a characteristic of conventional NSAIDs--thecompounds of this invention nonetheless have antiproliferative effectson precancerous lesion cells.

DETAILED DESCRIPIION OF THE INVENTION

As discussed above, the present invention includes the compounds belowfor treating a patient with precancerous lesions: ##STR1##

X can be carbon, or R⁶ --X equals nitrogen.

R₁ and R₂ are independently selected from the group consisting ofhydrogen, amino, lower alkyl, lower alkoxy, azide, hydroxy, halogen,acetoxyl, benzoxyl, or substituted phenyl where the substituents areselected from the group consisting of halogen, lower alkyl, or loweralkoxy; or R₁ and R₂ form a carbonyl or imine; or

R₂ and R₃ together form a double bond, aziridin, epoxide or triazole; ora dioxolane,

R₃ is selected from the group consisting of hydrogen, halogen, azide,lower alkyl, lower alkoxy, di(lower)alkyl amino(lower)alkoxy, cyano,hydroxy, di(lower)alkyl amino(lower)alkylthio, loweralkylthio,phenylthio, or di(lower)alkyl amino. R₃ is further selected from a groupof sulfur containing acids and peptides, which are coupled by their thiogroup. Preferred compounds are mercaptoacetic acid, cysteine,N--Ac-cysteine and glutathione.

R₄ is selected from the group consisting of hydrogen, hydroxy, halogen,lower alkoxy or lower alkyl, or lower dialkyl amino.

R₅ is selected from the group consisting of hydrogen, hydroxy, halogen,lower alkoxy, lower alkyl, amino, or lower dialkyl amino.

R₆ is selected from the group consisting of hydrogen, lower alkyl,hydroxy, lower alkoxy, halogen or R₆ and R₈ together from a double bond.

R₇ is selected from the group consisting of hydrogen, lower alkyl,phenyl, halo(lower)alkyl, hydroxy(lower)alkyl, acetoxy(lower)alkyl,benzyloxy(lower)alkyl, or (lower)alkyl(lower)alkoxy, or(lower)dialkylamino(lower)alkyl.

R₈ and R₉ are independently selected from the group consisting ofhydrogen, lower alkyl, hydroxy, lower alkoxy, or halogen; or

R₈ & R₉ together may be oxygen.

R₁₀ and R₁₁ are independently selected from the group consisting ofhydrogen, halogen, lower alkoxy, or lower alkyl.

R₁₂ is selected from the group consisting of hydrogen, halogen, loweralkyl, lower alkoxy, loweralkylthio, loweralkylsulfinyl, lower alkylsulfonyl, or amidosulfonyl.

Preferred compounds of this invention include those when X is carbonwhere R₁ and R₂ are independently selected from the group consisting ofhydrogen, amino, lower alkyl, lower alkoxy, azide, hydroxy, or halogen,or R₁ and R₂ form a carbonyl; or R₂ and R₃ form a double bond, aziridin,epoxide, triazole or dioxolane;

R₄ and R₅ are selected from the group consisting of hydrogen, halogen orlower alkoxy;

R₆ is hydrogen or together with R₈ forms a double bond;

R₇ is selected from the group consisting of hydrogen, lower alkyl,halo(lower)alkyl, hydroxy(lower)alkyl, acetoxy(lower)alkyl,benzyloxy(lower)alkyl, or (lower)alkyl(lower)alkoxy; and

R₈ -R₁₁ are hydrogen.

When X is nitrogen, preferred compounds of this invention include thosewhere R₁ and R₂ are independently selected from the group consisting ofhydrogen, amino, lower alkyl, lower alkoxy, azide, hydroxy, or halogen,or R₁ and R₂ form a carbonyl; or R₂ and R₃ form a double bond, aziridin,epoxide, triazole or dioxolane;

R₄ and R₅ are independently selected from the group consisting ofhydrogen, halogen or lower alkoxy;

R₇ is selected from the group consisting of hydrogen, lower alkyl,halo(lower)alkyl, hydroxy(lower)alkyl, acetoxy(lower)alkyl,benzyloxy(lower)alkyl, or (lower)alkyl(lower)alkoxy;

R₈ and R₉ together are an oxygen; and

R₁₀ -R₁₁ are hydrogen.

The present invention also is a method of treating a patient withprecancerous lesions by administering a physiologically effective amountof the following compounds (preferably in the absence of an NSAID) to apatient in need of such treatment: ##STR2##

X can be carbon, or R⁶ --X equals nitrogen.

R₁ and R₂ are independently selected from the group consisting ofhydrogen, amino, lower alkyl, lower alkoxy, azide, hydroxy, halogen,acetoxyl, benzoxyl, or phenyl or substituted phenyl where thesubstituents are selected from the group consisting of halogen, loweralkyl, or lower alkoxy; or R₁ and R₂ form a carbonyl or imine; or

R₂ and R₃ together form a double bond, aziridin, epoxide or triazole; ora dioxolane,

R₃ is selected from the group consisting of hydrogen, halogen, azide,lower alkyl, lower alkoxy, di(lower)alkyl amino(lower)alkoxy, cyano,hydroxy, di(lower)alkyl amino(lower)alkylthio, loweralkylthio,phenylthio, or di(lower)alkyl amino. R₃ is further selected from a groupof sulfur containing acids and peptides, which are coupled by their thiogroup. Preferred compounds are mercaptoacetic acid, cysteine,N--Ac-cysteine and glutathione.

R₄ is selected from the group consisting of hydrogen, hydroxy, halogen,lower alkoxy or lower alkyl, or lower dialkyl amino.

R₅ is selected from the group consisting of hydrogen, hydroxy, halogen,lower alkoxy, lower alkyl, amino, or lower dialkyl amino.

R₆ is selected from the group consisting of hydrogen, lower alkyl,hydroxy, lower alkoxy, halogen or R₆ and R₈ together from a double bond.

R₇ is selected from the group consisting of hydrogen, lower alkyl,phenyl, halo(lower)alkyl, hydroxy(lower)alkyl, acetoxy(lower)alkyl,benzyloxy(lower)alkyl, or (lower)alkyl(lower)alkoxy, or(lower)dialkylamino(lower)alkyl.

R₈ and R₉ are independently selected from the group consisting ofhydrogen, lower alkyl, hydroxy, lower alkoxy, or halogen; or

R₈ & R₉ together may be oxygen.

R₁₀ and R₁₁ are independently selected from the group consisting ofhydrogen, halogen, lower alkoxy, or lower alkyl.

R₁₂ is selected from the group consisting of hydrogen, halogen, loweralkyl, lower alkoxy, loweralkylthio, loweralkylsulfinyl, lower alkylsulfonyl, or amidosulfonyl.

The present invention is also a method of treating individuals withprecancerous lesions by administering a pharmaceutically effectiveamount of an enterically coated compounds of this invention.

As used herein, the term "precancerous lesion" includes syndromesrepresented by abnormal neoplastic, including dysplastic, changes oftissue. Examples include adenomatous growths in colonic, breast or lungtissues, or conditions such as dysplastic nevus syndrome, a precursor tomalignant melanoma of the skin. Examples also include, in addition todysplastic nevus syndromes, polyposis syndromes, colonic polyps,precancerous lesions of the cervix (i.e., cervical dysplasia), prostaticdysplasia, breast and/or skin and related conditions, whether thelesions are clinically identifiable or not.

As used herein, the term "carcinomas" refers to lesions which arecancerous. Examples incloude malignant melanomas, breast cancer, andcolon cancer.

As used herein, the term "neoplasm" refers to both precancerous andcancerous lesions.

As used herein, the term "halo" or "halogen" refers to chloro, bromo,fluoro and iodo groups, and the term "alkyl" refers to straight,branched or cyclic alkyl groups. The term "lower alkyl" refers to C₁ toC₈ alkyl groups.

Compounds of this invention may be formulated into compositions togetherwith pharmaceutically acceptable carriers for oral administration insolid or liquid form, or for rectal administration, although carriersfor oral administration are most preferred.

Pharmaceutically acceptable carriers for oral administration includecapsules, tablets, pills, powders, troches and granules. In such soliddosage forms, the carrier can comprise at least one inert diluent suchas sucrose, lactose or starch. Such carriers can also comprise, as isnormal practice, additional substances other than diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, troches and pills, the carriers may also comprise bufferingagents. Carriers such as tablets, pills and granules can be preparedwith enteric coatings on the surfaces of the tablets, pills or granules.Alternatively, the enterically coated compound can be pressed into atablet, pill, or granule, and the tablet, pill or granules foradministration to the patient. Preferred enteric coatings include thosethat dissolve or disintegrate at colonic pH such as shellac or EudragetS.

Pharmaceutically acceptable carriers include liquid dosage forms fororal administration , e.g. pharmaceutically acceptable emulsions,solutions, suspensions, syrups and elixirs containing inert diluentscommonly used in the art, such as water. Besides such inert diluents,compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring andperfuming agents.

Pharmaceutically acceptable carriers for rectal administration arepreferably suppositories which may contain, in addition to the compoundsof this invention excipients such as cocoa butter or a suppository wax.

The pharmaceutically acceptable carrier and compounds of this inventionare formulated into unit dosage forms for administration to a patient.The dosage levels of active ingredient (i.e. compounds of thisinvention) in the unit dosage may be varied so as to obtain an amount ofactive ingredient effective to achieve lesion-eliminating activity inaccordance with the desired method of administration (i.e oral orrectal). The selected dosage level therefore depends upon the nature ofthe active compound administered, the route of administration, thedesired duration of treatment, and other factors. If desired, the unitdosage may be such that the daily requirement for active compound is inone dose, or divided among multiple doses for administration, e.g. twoto four times per day.

The pharmaceutical compositions of this invention are preferablypackaged in a container (e.g. a box or bottle, or both) with suitableprinted material (e.g. a package insert) containing indications,directions for use, etc.

In another form, the invention is a method of inhibiting the growth ofneoplastic cells by exposing them to an effective amount of the compoundof formula I! above.

The foregoing may be better understood from the following examples,which are presented for purposes of illustration and are not intended tolimit the scope of the invention. As used in the following examples, thereferences to substituents such as R, R₁, R₂ etc., refer to thecorresponding compounds and substituents in the formula I above. Inexamples 1 through 34, X is carbon.

EXAMPLE 1 rac-threo-(E)-1-Bromo-1-(Butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene-indan (A)p-Fluoro-α-methylcinnamic acid.

p-Fluorobenzaldehyde (200 g, 1.61 mol), propionic anhydride (3.5 g, 2.42mol) and sodium propionate (155 g, 1.61 mol) are mixed in a 1 lthree-necked flask which had been flushed with nitrogen. The flask isheated gradually in an oil-bath to 140°. After 20 h, the flask is cooledto 100°and poured into 8 l of water. The precipitate is dissolved byadding potassium hydroxide (302 g) in 2 l of water. The aqueous solutionis extracted with ether, and the ether extracts washed with potassiumhydroxide solution. The combined aqueous layers are filtered, areacidified with concentrated HCl, and are filtered. The collected solid,p-fluoro-α-methylcinnamic acid, is washed with water, and is dried andused as obtained.

(B) p-Fluoro-α-methylhydrocinnamic acid.

To p-fluoro-α-methylcinnamic acid (177.9 g, 0.987 mol) in 3.6 l ethanolis added 11.0 g of 5% Pd/C. The mixture is reduced at room temperatureunder a hydrogen pressure of 40 p.s.i. When hydrogen uptake ceases, thecatalyst is filtered off, and the filtrate is concentrated in vacuo togive the product, p-fluoro-α-methylhydrocinnamic acid, which was usedwithout weighing in the next step.

(C) 6-Fluoro-2-methylindanone

To 932 g polyphosphoric acid at 70° C. (on the steam bath) is addedp-fluoro-α-methylhydrocinnamic acid (93.2 g, 0.5 mol) slowly withstirring. The temperature is gradually raised to 95° C., and the mixtureis kept at this temperature for 1 hour. The mixture is allowed to cooland added to 2 l of water. The aqueous layer is extracted with ether,the ether solution is washed twice with saturated sodium chloridesolution, 5% Na₂ CO₃ solution, water, and is then dried. The etherfiltrate is concentrated with 200 g silica-gel, and is added to a fivepound silica-gel column packed with 5% ether-petroleum ether. The columnis eluted with 5-10% ether-petroleum ether, to give6-fluoro-2-methylindanone. Elution is followed by TLC.

(D) 5-fluoro-2-methylindanone-3-acetic acid

A mixture of 6-fluoro-2-methylindanone (18.4 g, 0.112 g mol),cyanoacetic acid (10.5 g, 0.123 mol), acetic acid (6.6 g), and ammoniumacetate (1.7 g) in dry toluene (15.5 ml) is refluxed with stirring for21 h, as the liberated water is collected in a Dean Stark trap. Thetoluene is concentrated, and the residue dissolved in 60 ml of hotethanol and 14 ml of 2.2N aqueous potassium hydroxide solution. 22 g of85% KOH in 150 ml of water is added, and the mixture refluxed for 13 hunder nitrogen. The ethanol is removed under vacuum, 500 ml water added,the aqueous solution is washed well with ether and then boiled withcharcoal. The aqueous filtrate is acidified to pH 2 with 50% coldhydrochloric acid. The precipitate and dried5-fluoro-2-methylindenyl-3-acetic acid (m.p. 164°-166° C.) is obtained.

(E) 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid

5-fluoro-2-methyl-3-indenylacetic acid (15 g, 0.072 mol)p-methylthiobenzaldehyde (14.0 g, 0.091 mol) and sodium methoxide (13.0g, 0.24 mol) are heated in methanol (200 ml) at 60° under nitrogen withstirring for 6 h. After cooling, the reaction mixture is poured into 750ml of ice-water, and is acidified with 2.5N hydrochloric acid. Thecollected solid is triturated with a little ether to produce5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid (m.p.187°-188.2° C.).

(F) 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylaceticacid

To a solution of 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid (3.4 g, 0.01 mol) in a mixture of methanol (250 ml) andacetone (100 ml) is added a solution of sodium periodate (3.8 g, 0.018mol) in water (50 ml) with stirring.

Water (450 ml) is added after 18 h, and the organic solvents removedunder vacuum below 30° C. The precipitated product is filtered, driedand recrystallized from ethyl acetate to give5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid.Upon repeated recrystallization upon ethylacetate there is obtainedcis-5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylaceticacid, m.p. 184°-186° C.

Further runs reveal the existence of a second polymorph ofcis-5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenyl aceticacid, m.p. 179°-181° C.

(G) 5-fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylaceticacid

To 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylaceticacid (12.0 g, 33.66 mmol) in 140 ml THF is added gradually at 0° C. asolution of OXONE (12.47 g, 36.72 mmol) andtetrabutylammoniumhydrogensulfate (1.0 g, 1.62 mmol) in 35 ml H₂ O. Thetemperature of the reaction mixture is maintained in the range of13°-23° C. After 24 h at room temperature, the THF phase is separatedfrom the water phase and is dripped into water (280 ml, 40° C.). Thesuspension is stirred until it reaches room temperature. The yellowcrystals of5-fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acidare filtered off and are washed with water (30 ml). 11.3 g, 30.29 mmol,90% mp. 204°-206° C.

(H) rac-threo-(E)-1-Bromo-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

N-Bromosuccinimide (98%, 3×1.76 g, 29.8 mmol) is added to a stirredsolution of(Z)-5-fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylaceticacid (10 g, 26.9 mmol) in DMA/H₂ O (22 ml, 10:1). After 24 h at roomtemperature, the resulting suspension is added dropwise to stirredice-water (1000 ml). A pale yellow precipitate is filtered off, iswashed with water (500 ml), and is recrystallized fromdichloromethane/n-hexane to give white crystals ofrac-threo-(E)-1-Bromo-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (7.3g, 16.1 mmol, 60%). C₂₀ H₁₆ BrFO₄ S:451.31; mp. 195° C.

R₁ =hydrogen, R₂ =hydrogen, R₃ =bromo, R₄ =6-fluoro, R₅ =hydrogen, R₆and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 2 rac-threo-(E)-1-Bromo-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfinylbenzylidene)-indan

N-Bromosuccinimide (98%, 0.6 g, 4.4 mmol) is added to a stirred solutionof (Z)-5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylaceticacid (1 g, 2.8 mmol) in DMA/water (4 ml DMA/0.1 ml water). After 24 h atroom temperature, the resulting suspension is added dropwise to stirredice-water (100 ml). A pale yellow precipitate is filtered off, is washedwith water (50 ml), and is recrystallized from CH₂ Cl₂ /n-hexane to givewhite crystals of rac-threo-(E)-1-Bromo-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfinylbenzylidene)-indan (0.8g, 1.9 mmol, 73%). C₂₀ H₁₆ BrFO₃ S:435.30; mp. 162° C.

R₁ =hydrogen, R₂ =hydrogen, R₃ =bromo, R₄ =6-fluoro, R₅ =hydrogen, R₆and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfinyl.

EXAMPLE 3 rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

A solution of rac-threo-(E)-1-Bromo-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan fromExample 1 (7.3 g, 16.1 mmol) in CH₂ Cl₂ (50 ml) is treated withN,N-diisopropylethylamine (3.7 ml, 21.3 mmol) for 24 h at roomtemperature, is extracted with cold aqueous hydrochloric acid (10%,2×100 ml), and water (3×100 ml). The organic phase is dried (MgSO₄), andis evaporated. The residue is purified by flash chromatography (SiO₂,CHCl₃ :Methylisobutylketone 8:2, R_(f) =0.65), to give white crystals ofrac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (3.9g, 10.6 mmol, 66%). C₂₀ H₁₅ FO₄ S: 370.40; mp. 193° C.

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-fluoro, R₅ =hydrogen,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 4 rac-(E)-1-(2'-Buten-1',4'-olido)-3,'4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfinylbenzylidene)-indan

A solution of rac-threo-(E)-1-bromo-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfinylbenzylidene)-indan fromExample 2 (0.8 g, 1.9 mmol) in CH₂ Cl₂ (80 ml) is treated withN,N-diisopropylethylamine (0.6 ml, 3.5 mmol) for 24 h at roomtemperature, is extracted with cold aqueous hydrochloric acid (10%, 2×10ml), and water (3×10 ml). The organic phase is dried (MgSO₄), and isevaporated. The residue is purified by flash chromatography (SiO₂, CHCl₃:Methylisobutylketone 8:2), to give white crystals ofrac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfinylbenzylidene)-indan (0.5g, 1.4 mmol, 74%). C₂₀ H₁₅ FO₃ S: 354.40; mp. 84° C.

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-fluoro, R₅ =hydrogen,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R ₁₁=hydrogen, and R₁₂ =methylsulfinyl.

EXAMPLE 5 rac-threo-(E)-1-Chloro-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

To a stirred solution of rac-(E)-1-(2'-buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan fromExample 3 (1 g, 2.7 mmol) in THF (30 ml) is added hydrochloric acid (10ml, 37%). After five days at room temperature, the solution is addeddropwise with stirring to ice-water (500 ml). A precipitate is filteredoff, is washed with water (200 ml), and recrystallized from chlorinatedsolvents to give white crystals ofrac-threo-(E)-1-chloro-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (0.67g, 1.6 mmol, 61%). C₂₀ H₁₆ ClFO₄ S: 406.85; mp. 177° C.

R₁ =hydrogen, R₂ =hydrogen, R₃ =chloro, R₄ =6-fluoro, R₅ =hydrogen, R₆and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 6 rac-threo-(E)-1-Acetoxy-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan fromExample 3 (1 g, 2.7 mmol) and NH₄ Ac (5 g, 64.8 mmol) are meltedtogether at 125° C. for two h. Water (100 ml) is added to the cooledmixture. A precipitate is filtered off, and is washed with water (100ml). By crystalliztion from methanol, it gives white crystals ofrac-threo-(E)-1-acetoxy-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (0.53g, 1.23 mmol, 46%). C₂₂ H₁₉ FO₆ S: 430.44; mp. 187° C.

R₁ =hydrogen, R₂ =hydrogen, R₃ =acetoxy, R₄ =6-fluoro, R₅ =hydrogen, R₆and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 7 rac-threo-(E)-1-Azido-1-(butan-1',4'-olido)-3,'4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

A solution of rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan fromExample 3 (1.0 g, 2.7 mmol) in DMF (10 ml) is stirred with NaN₃ (0.2 g,3 mmol) for 80 min at room temperature, diluted with water (30 ml), andacidified at 0° C. (pH=4, 10% HCl). A yellow precipitate is filteredoff, is washed with water, and is chromatographed (SiO₂, ethylacetate)to give white crystals of rac-theo-(E)-1-azido-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfinylbenzylidene)-indan (0.2g, 0.5 mmol, 19%). C₂₀ CH₁₆ FN₃ O₄ S: 413.42; mp. 137° C.

R₁ =hydrogen, R₂ =hydrogen, R₃ =azido, R₄ =6-fluoro, R₅ =hydrogen, R₆and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂₌ methylsulfonyl.

EXAMPLE 8 rac-threo-(E)-1-Methoxy-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(lp-methylsulfonylbenzylidene)-indan

A suspension of rac-(E)-1-(2'-buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan fromExample 3 (1.0 g, 2.7 mmol) in MeOH (30 ml) is stirred with methanolic1N NaOCH₃ (3 ml) for 24 h at room temperature. A white solid is filteredoff, is washed with H₂ O (50 ml), and from MeOH gives white crystals ofrac-theo-(E)-1-methoxy-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (0.81g, 2.0 mmol, 75%). C₂₁ H₁₉ FO₄ S: 402.43; mp. 196° C.

R₁ =hydrogen, R₂ =hydrogen, R₃ =methoxy, R₄ =6-fluoro, R₅ =hydrogen, R₆and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 9 rac-(E)-1-(Butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

A stirred solution of rac-threo-(E)-bromo-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan fromExample 1 (1 g, 2.2 mmol) in 5 ml DMF is treated with portions of NaBH₄(5×0.04 g in 4 hr intervals) at room temperature. The solution is thenadded slowly to 5% stirred aqueous Hcl (100 ml). A white solid isfiltered off, is washed with water (200 ml), and from MeOH gives whitecrystals of rac-(E)-1-(Butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (0.65g, 1.7 mmol, 80%). C₂₀ H₁₇ FO₄ S: 372.40; mp. 195° C.

R₁ =hydrogen, R₂ =hydrogen, R₃ =hydrogen, R₄ =6-fluoro, R₅ =hydrogen, R₆and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 10 rac-lyxo-(E)-1-(Butan-1',4'-olido)-2'3'-(Z)-dihydroxy-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

A solution of rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan fromExample 3 (1 g, 2.7 mmol) in CH₂ Cl₂ (20 ml) is treated with 1 ml waterand with OsO₄ (0.054 mmol, 1.08 ml solution in t-BuOH) andN-methylmorpholine-N-oxide (0.46 ml, 2.73 mmol) under a nitrogenatmosphere. After five h at room temperature, aqueous Na₂ SO₃ (1.35 g,10.7 mmol) in 8 ml water is added with stirring. After two h, thereaction mixture is extracted with CH₂ Cl₂. The organic phase is washedwith H₂ O (3×50 ml), is dried (Na₂ SO₄) and is evaporated. The residuegives white crystals ofrac-lyxo-(E)-1-(Butan-1',4'-olido)-2',3'-(Z)-dihydroxy-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (0.75g, 1.5 mml, 70%) from MeOH. C₂₀ H₁₇ FO₆ S: 403.40; mp. 128° C.

R₁ =hydrogen, R₂ =hydroxy, R₃ =hydroxy, R₄ =6-fluoro, R₅ =hydrogen, R₆and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 11 rac-threo-(E)-1-Hydroxy-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan fromExample 3 (1 g, 2.7 mmol) in 30 ml CH₂ Cl₂ is treated with Bu₄ NOH (Bu₄NHSO.sub.₄ 0.34 g, 1 mmol; NaOH 0.4 g, 10 mmol; 10 ml H₂ O). After fivedays at room temperature, the aqueous phase is separated, and isacidified at 0° C. (pH 4, citric acid). The reaction mixture isextracted with CH₂ Cl₂. The organic phase is washed with H₂ O, is dried(Na₂ SO₄) and is evaporated. The residue gives white crystals from CH₂Cl₂ /n-hexane: 0.30 g, 0.8 mmol, 30%.

R₁, R₂ =hydrogen, R₃ =OH, R₄ =6-fluoro, R₅ =hydrogen, R₆ and R₈ form adouble bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁ =hydrogen, and R₁₂=methylsulfonyl. C₂₀ H₁₇ O₅ SF: 388.41. mp. 93° C.

EXAMPLE 12rac-threo-(E)-1-(N,N'-diethylaminoethanethio)-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan fromExample 3 (1 g, 2.7 mmol) in 20 ml DMF/1 ml glacial acetic acid istreated with 2-diethylamioethanethiol•HCl (0.49 g, 2.9 mmol) at roomtemperature. After 10 days, the reaction mixture is added to 200 g ice.A precipitate is filtered off. The filtrate is neutralized with NaHCO₃(5% in water). A white precipitate is filtered off, is washed with water(200 ml), and is recrystallized from CH₂ Cl₂ /n-hexane to give whitecrystals: 0.56 g, 1.1 mmol, 41% mp. 69° C.

R₁, R₂ =hydrogen, R₃ =S--CH₂ CH₂ --N(Et)₂, R₄ =6-fluoro, R₅ =hydrogen,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl. C₂₆ H₃₀ FNO₄ S₂ : 503.64.

EXAMPLE 13 rac-threo-(E)-1-Cyano-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan fromExample 3 (1 g, 2.7 mmol) in 20 ml DMF is added to a solution of NaCN(0.3 g, 6 mmol) in 30 ml DMF/5 ml glacial acetic acid at roomtemperature. After 7 days, the reaction mixture is added to 200 g ice. Awhite precipitate is filtered off, is washed with water (200 ml), and isrecrystallized from MeOH to give crystals. 0.84 g, 2.1 mmol, 78% mp.224° C.

R₁, R₂ =hydrogen, R₃ =CN, R₄ =6-fluoro, R₅ =hydrogen, R₆ and R₈ form adouble bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁ =hydrogen, and R₁₂=methylsulfonyl. C₂₁ H₁₆ NO₄ SF: 397.42.

EXAMPLE 14 rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-5.6-difluoro-2-methyl-3-(p-methylsulfinylbenzylidene)-indan(A) 3,4-difluorobenzaldehyde

In a 250 ml three-necked flask equipped with a magnetic stirrer,thermometer, condenser, and dropping funnel is placed 25.6 g (0.2 mol)of 3,4-difluorotoluene. The liquid is heated to 105° and illuminated as67 g (0.42 mol) of bromine is added slowly. The temperature is keptbetween 105°-110° C. while the first half of the bromine is added over aperiod of one hour. The rest of the bromine is added over approx. a 2hour period, and the temperature is raised to 150° and kept there for 5minutes. The reaction mixture is cooled and transferred to a 1 liter3-necked flask with a motor driven stirrer and condenser. 120 ml H₂ Oand 90 g of calcium carbonate are added, and the mixture is refluxed for20 h with good stirring. The reaction mixture is steam distilled untilno further oil is collected. The oil is taken up in methylene chlorideand dried over MgSO₄. Evaporation of the solvent yields3,4-difluorobenzaldehyde which is used without further purification.

(B) 3,4-difluoro-α-methylcinnamic acid

A mixture of 2.88 g (0.02 mol) of 3,4-difluorobenzaldehyde, 3.24 g(0.025 mol) of propionic anhydride and 0.92 g (0.02 mol) of sodiumpropionate under nitrogen is heated at 135° C. with magnetic stirrer for20 h. The reaction mixture is poured onto 50 ml of water. A solidprecipitates, which dissolves when 50 ml of saturated K₂ CO₃ is addedwith stirring. The basic solution is extracted with ether (2×100 ml).The aqueous phase is then poured into an excess of concentrated HCl andice. The precipitated white solid is filtered and dried to give3,4-difluoro-α-methylcinnamic acid, m.p. 122°-125° C.

(C) 3,4-difluoro-α-methylhydrocinnamic acid

28 g (0.141 mol) of 3,4-difluoro-α-methylcinnamic acid, 1 g of PtO₂ in250 ml of MeOH is hydrogenated at 45 p.s.i. until the theoretical uptakeis completed. The catalyst is filtered off, and the material evaporatedto one-third its volume. A 15% potassium hydroxide solution (10 ml) isadded, and the mixture refluxed for 30 minutes when it is poured intowater and extracted with ether (2×100 ml). The aqueous layer isacidified with concentrated HCl and ice. The oil which comes out isextracted into ether, the ether solution dried over MgSO₄ and evaporatedto leave a clear oil which crystallizes.3,4-difluoro-αmethylhydrocinnamic acid, m.p. 55°-56° C., is isolated.

(D) 5,6-difluoro-2-methyl-1-indanone

20 g (0.1 mol) of 3,4-difluoro-α-methylhydrocinnamic acid is added to250 g of polyphosphoric acid. The mixture is efficiently stirred andheated on a steam bath for 2 h. The mixture is poured onto ice-water(400 ml). The precipitate is extracted with ether (3×100 ml). Theextract is washed with saturated potassium carbonate, water and thendried (MgSO₄). The ether solution when evaporated leaves solid5,6-difluoro-2-methyl-1-indanone (m.p. 66°-68° C.) which is used withoutfurther purification.

(E) 5,6-difluoro-2-methylindene-3-acetic acid, methyl ester

A mixture of 9.1 g (0.05 mol) of 5,6-difluoro-2-methyl-1-indanone, 4.0 gof "activated" zinc dust, 7.6 g (0.05 mol) of methyl bromoacetate and acrystal of iodine in 250 ml of dry benzene is refluxed for 4-5 h. TLC(20% Et₂ O 80% pet. ether on Si gel) shows greater than 95% conversionat this time. The reaction mixture is poured onto 250 ml of 5% H₂ SO₄,separated, and dried (MgSO₄). Removal of solvent leaves an oily hydroxyester. The crude ester is redissolved in 100 ml of benzene andphosphorus pentoxide (20 g) is added. The mixture is refluxed for 30minutes (no stirrer necessary) and decanted. The residue is washed withbenzene, the organic layers are combined, are washed with water (2×100ml) and are dried (MgSO₄). The benzene when evaporated leaves5,6-difluoro-2-methylindene-3-acetic acid, methyl ester, m.p. 86°-90° C.

(F) 5,6-difluoro-2-methyl-1-(p-methylthiobenzylidene)-indene-3-aceticacid)

1.19 g (5.0 mmol) of 5,6-difluoro-2-methylindene-3-acetic acid methylester is dissolved in 10 ml of dry pyridine followed by 0.76 g (5.0mmol) of p-methylthiobenzaldehyde. The flask is placed under nitrogen,and 5.0 g (5.1 mmol) of Triton B is added. The deeply colored solutionis allowed to stand overnight, and then 2 ml of water is added. Afterstanding for 15 minutes, it is poured into an excess of water. Theorganics are extracted with ether (2×50 ml). The aqueous phase is addedto 10% HCl-ice. The orange gummy solid which precipitates is extractedinto methylene chloride and dried (MgSO₄). The solvent is removed toleave an orange solid. The solid is filtered to give a crude productwhich is recrystallized from benzene to give5,6-difluoro-2-methyl-1-(p-methylthiobenzylidene)-indene-3-acetic acid.m.p. 181°-182.5° C.

(G)(Z)-5,6-difluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-3-aceticacid

To a solution of 0.358 g (1.0 mmol) of5,6-difluoro-2-methyl-1-(p-methylthiobenzylidene)-indene-3-acetic acidin acetone (10 ml) is added 10-15 ml MeOH. With magnetic stirring 0.32 g(1.5 mmol) of sodium meta periodate is added in 5 ml of water. Theproportions of acetone, methanol and water are adjusted if necessary inorder to preserve homogeneity. After several minutes, a precipitation ofsodium iodate appears. The suspension is stirred at room temperature for16 h, and is then poured into approximately 50 ml of water and 100 mlmethylene chloride. The two phases are separated and extracted twicewith methylene chloride. The organic layer is washed with water anddried (MgSO₄). The residue after evaporation is dissolved in the minimumamount of boiling ethyl acetate and is allowed to stand for 12 h in thefreezer compartment. The deep orange crystals are filtered. The filtrateis reduced to 1/2 volume and allowed to stand in the cold for severalhours to give a large second crop. In this way,5,6-difluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylaceticacid is isolated, m.p. 200°-210° C.

(H) rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-5,6-difluoro-2-methyl-3-(p-methylsulfinylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-5,6-difluoro-2-methyl-3-(p-methylsulfinylbenzylidene)-indanis obtained, if(Z)-5,6-difluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylaceticacid is reacted according to the procedures of Example 2 and Example 4.C₂₀ OH₁₄ F₂ O₃ S:372.38.

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-fluoro, R₅ =5-fluoro,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, and R₁₂=methylsulfinyl.

EXAMPLE 15 rac-(E)-1-(2'-Buten-1',4'-olido)3',4':1,2!-5.6-difluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan(A)(Z)-5,6-difluoro-2-methyl-1-(p-methylsulfonylbenzylindene)-indene-3-aceticacid

To(Z)-5,6-difluoro-2-methyl-1-(p-methylsulfinylbenzylindene)-indene-3-aceticacid (0.005 mol) in acetone (15 ml) is added, slowly with stirring,m-chloroperbenzoic acid (0.005 mol). The mixture is heated andevaporated to near dryness at 40° C. The solid is leached with boilingwater (4×50 ml) and dried yielding5,6-difluoro-2-methyl-1-(p-methylsulfonylbenzylindene)-indene-3-aceticacid, m.p. 228°-230° C.

(B) rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-5,6-difluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-5,6-difluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indanis obtained, if(Z)-5,6-difluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylaceticacid is reacted according to the procedure of Example 1 and Example 3.

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-fluoro, R₅ =5-fluoro,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, and R₁₂=methylsulfonyl.

EXAMPLE 16 rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-dimethylamino-2-methyl-3-(p-methylsulfinylbenzylidene)-indan(A) Methyl 3-hydroxy-2-methyl-5-nitro-3-indenyl-acetate

A solution of 13.4 g of 2-methyl-6-nitroindanone and 19.3 g of methylbromoacetate in 45 ml benzene is added over a period of 5 minutes to 21g of zinc amalgam (prepared according to Org. Syn. Coll., Vol. 3) in 110ml benzene and 40 ml dry ether. A few crystals of iodine are added tostart the reaction, and the reaction mixture is maintained at refluxtemperature (ca. 650) with external heating. At three-hour intervals,two batches of 10 g zinc amalgam and 10 g bromoester are added, and themixture is then refluxed for 8 h. After addition of 30 ml of ethanol and150 ml of acetic acid, the mixture is poured into 700 ml of 1:1 aqueousacetic acid. The organic layer is separated, and the aqueous layer isextracted twice with ether. The combined organic layers are washedthoroughly with water, ammonium hydroxide and water. The hydroxy esterproduct is dried over sodium sulfate. Evaporation of solvent in vacuo isfollowed by pumping at 80° (bath temp.) (1-2 mm).

A mixture of the above crude hydroxyester, 20 g of p-toluenesulfonicacid monohydrate and 20 g of anhydrous calcium chloride in 250 mltoluene is refluxed overnight. The solution is filtered, and the solidresidue is washed with benzene. The combined benzene solution is washedwith water, sodium bicarbonate, water and is then dried over sodiumsulfate. After the mixture is condensed, 30 ml of ethanol and 50 ml ofacetic acid are added. The mixture is then poured into 700 ml of water.Extraction with ether gives methyl3-hydroxy-2-methyl-5-nitro-3-indenylacetate.

(B) Methyl 5-dimethylamino-2-methyl-3-indenylacetate

A solution of 0.05 mol of methyl3-hydroxy-2-methyl-5-nitro-3-indenylacetate, 0.2 mol of 38% aqueousformaldehyde and 2 ml of acetic acid in 100 ml ethanol is reducedcatalytically in the presence of a 10% Pd/C catalyst under 40 lb. p.s.i.hydrogen pressure at room temperature. The solution is filtered,evaporated and chromatographed on 300 g of silica gel to give methyl5-methylamino-3-hydroxy-2-methyl-3-indenylacetate. The hydroxy ester isthen dehydrated to methyl 5-dimethylamino-2-methyl-3-indenylacetate.

(C) 1-p-methylthiobenzylidene-5-dimethylamino-2-methyl-3-indenyl aceticacid

To a solution of 2.5 g of the ester from Part B of this example in 15 mlof 1,2-dimethoxyethane at 0° is added 1.5 g of p-methylthiobenzaldehydefollowed by 1.1 g of potassium t-butoxide. The reaction mixture is keptin the ice-bath for 4 h and is then allowed to stand at room temperaturefor 18 h. The mixture is diluted with 15 ml of ether and the potassiumsalt is filtered. The salt is dissolved in 30 ml of water andneutralized with dilute hydrochloric acid to pH 6-6.5. The crude acidprecipitated is collected by filtration and chromatographed on a silicagel column, using ether-petroleum ether (v./v. 50-100%) as eluent togive pure1-p-methylthiobenzylidene-5-dimethylamino-2-methyl-3-indenylacetic acidwhich may be oxidized to1-p-methylsulfinylbenzylidene-5-dimethylamino-2-methyl-3-indenylaceticacid and1-p-methylsulfonylbenzylidene-5-dimethylamino-2-methyl-3-indenylaceticacid as described above (Example 1).

(D) rac-(E)-1-(2'-buten-1',4'-olido)-3',4':1,2!-6-dimethylamino-2-methyl-3-(p-methylsulfinylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-dimethylamino-2-methyl-3-(p-methylsulfinylbenzylidene)-indanis obtained, if(Z)-5-dimethylamino-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylaceticacid from part (C) is reacted according to the procedure of Example 2and Example 4. C₂₂ H₂ lNO₃ S:379.47.

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-dimethylamino, R₃=hydrogen, R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, andR₁₂₌ methylsulfinyl.

EXAMPLE 17 rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-dimethylamino-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-dimethylamino-2-methyl-3-(p-methylsulfonylbenzylidene)-indanis obtained, if(Z)-5-dimethylamino-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylaceticacid from Example 16C is reacted according to the procedure of Example 1and Example 3. C₂₂ H₂₁ NO₄ S:395.47.

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-dimethylamino, R₅=hydrogen, R₆ and R₈ form a double bond, R₇ =methyl, R=hydrogen, andR₁₂₌ methylsulfonyl.

EXAMPLE 18 rac-(E)-1-(2'-Buten-1',4'-olido)3',4':1,2!-6-methoxy-2-methyl-3-(p-methylsulfinylbenzylidene)-indan (A)α-Methyl-β-(p-methoxyphenyl)propionic acid

To a solution of 2.3 g (0.1 mol) of sodium in 100 ml of absolute alcoholis added 17.4 g (0.1 mol) of diethyl methylmalonate and 17.3 g (0.1 mol)of p-methoxybenzylchloride. The mixture is heated under reflux in awater bath for 3 h. The reaction mixture is poured into water, and theaqueous solution is extracted six times with ether and dried. It is thenevaporated to yield diethyl methyl-p-methylthiobenzyl malonate. Thecrude product is then saponified by heating with excess 4% sodiumhydroxide in aqueous ethanolic solution. The solution thus formed isconcentrated, extracted with ether to remove any neutral material, andacidified with dilute sulfuric acid. The acidic mixture is heated on asteam bath for one hour, cooled and then extracted with ether.Evaporation of the ether solution givesα-methyl-β-(p-methoxyphenyl)propionic acid.

(B) 6-methoxy-2-methylindanone

α-Methyl-β-(p-methoxyphenyl)propionic acid (15 g) is added to 170 g ofpolyphosphoric acid at 50° and the mixture is heated at 83°-90° for 2 h.The syrup is poured into iced water, stirred for one-half hour and thenextracted with ether three times. The ether solution is washed withwater twice and 5% NaHCO₃ five times until all the acidic material hasbeen removed. The remaining neutral solution is washed with water anddried over sodium sulfate. Evaporation of the solution gives theindanone as a pale yellow oil.

(C) Methyl 5-methoxy-2-methyl-3-indenylacetate

A solution of 13.4 g of 6-methoxy-2-methylindanone and 19.3 g of methylbromoacetate in 45 ml benzene is added over a period of 5 minutes to 21g of zinc amalgam (prepared according to Org. Syn. Coll., Vol. 3) in 110ml benzene and 40 ml dry ether. A few crystals of iodine are added tostart the reaction, and the reaction mixture is maintained at refluxtemperature (ca. 65°) with external heating. At three-hour intervals twobatches of 10 g zinc amalgam and 10 g bromoester are added, and themixture is then refluxed for 8 h. After addition of 30 ml of ethanol and150 ml of acetic acid, the mixture is poured into 700 ml of 1:1 aqueousacetic acid. The organic layer is separated, and the aqueous layer isextracted twice with ether. The combined organic layers are washedthoroughly with water, ammonium hydroxide and water. Drying over sodiumsulfate, evaporation of solvent in vacuo followed by pumping at 80°(bath temp.) (1-2 mm) gives crude methyl(1-hydroxy-2-methyl-6-methoxy-indanyl)acetate.

A mixture of the above crude hydroxyester, 20 g of p-toluenesulfonicacid monohydrate and 20 g of anhydrous calcium chloride in 250 mltoluene is refluxed overnight. The solution is filtered and the solidresidue is washed with benzene. The combined benzene solution is washedwith water, sodium bicarbonate, water and is then dried over sodiumsulfate. After evaporation, the crude methyl5-methoxy-2-methyl-3-indenylacetate is chromatographed on acid-washedalumina, and the product is eluted with petroleum ether-ether (v./v.50-100%).

(D) 5-methoxy-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid

To a solution of methyl 5-methoxy-2-methyl-3-indenylacetate 8.7 g (0.037mol) and p-methylthiobenzaldehyde, 6.3 g (1.1. equivalent) is added 16ml (2.0 equivalents) of 25% methanolic sodium methoxide. The mixture isstirred at reflux under nitrogen for 2 h. An equal volume of water isadded dropwise and refluxing is continued for 30 min. The solution iscooled, is diluted with water and is extracted with ether. Residualether is blown off with nitrogen. The aqueous solution is acidified with50% glacial acetic acid. The precipitated product is collected and iswashed thoroughly with water. The crude product is crystallized frommethanol to give pure5-methoxy-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid(m.p. 195°-196°).

(E) 5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylaceticacid

A solution of sodium periodate (0.214 g) (0.001 mol) in 3 ml of water isadded dropwise to5-methoxy-2-methyl-1-(p-methylthiobenzyidene)-3-indenylacetic acid(0.352 g) (0.001 mol) in 25 ml methanol and enough acetone to causesolution. This solution is stirred overnight at room temperature and isfiltered. The filtrate is evaporated at 30° to a small volume whichcauses the product to precipitate. The suspension is diluted withseveral volumes of water and is cooled. The collected product is driedin vacuo over potassium hydroxide pellets and then in a vacuum oven at70° to give5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid(m.p. 200.5°-203.5°).

5-methoxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acidis prepared by the addition of 1.0 mol of m-chloroperbenzoic acid permol of5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acidin an acetone solution.

(F) rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-methoxy-2-methyl-3-(p-methylsulfinylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-methoxy-2-methyl-3-(p-methylsulfinylbenzylidene)-indan isobtained, if(Z)-5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylaceticacid is reacted according to the procedure of Example 2 and Example 4.C₂₁ H₁₈ O₄ S:366.43.

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-methoxy, R₅ =hydrogen,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfinyl.

EXAMPLE 19 rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1.2!-6-methoxy-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-methoxy-2-methyl-3-(p-methylsulfonylbenzylidene)-indan isobtained, if(Z)-5-methoxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylaceticacid from Example 18 part (E) is reacted according to the procedure ofExample 1 and Example 3. C₂₁ H₁₈ O₅ S:382.43.

R₁ =hydrogen, R₂ and R₃ form a double bond, R=6-methoxy, R₅ =hydrogen,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 20 rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-5-fluoro-6-methoxy-2-methyl-3-(p-methylsulfinylbenzylidene)-indan(A) 3-fluoro-4-methoxybenzaldehyde

To a solution of o-fluoroanisole, 101 g (0.80 mol) in 50 ml drymethylene chloride is added dropwise over 30 minute a solution oftitanium tetrachloride, 182 g (0.96 mol, 1.2 equiv.) andα,α-dichloromethylmethyl ether, 110 g (0.96 mol) in an equal volume ofmethylene chloride. The temperature is maintained at 10°-20° C. with anice-bath. The mixture is stirred at room temperature for one hourlonger, and then poured over crushed ice-water with stirring. Ether (1l) is added, and the mixture is stirred under nitrogen until solutionoccurs. The organic layer is extracted with water, sodium bicarbonatesolution and is dried (MgSO₄). The solvent is evaporated at 30° to leavecrude product as an oil. When vacuum distilled through a jacketedVigreux column, the oil gives 3-fluoro-4-methoxybenzaldehyde, B.P.120°-121° C. at 10 mm. Hg; R_(f) 0.6 on a silica-gel G plate withmethylene chloride.

(B) 3-fluoro-4-methoxy-α-methylcinnamic acid

A mixture of 3-fluoro-4-methoxybenzaldehyde, 34.2 g (0.22 mol),propionic anhydride, 50 g (0.38 mol) and sodium propionate, 21 g (0.22mol), is stirred under nitrogen at 150° C. for 15 h. The reactionmixture is then poured into 1.3 l of water with stirring and the productprecipitated. 2.0N potassium hydroxide solution (500 ml) is added, andthe mixture is stirred for several hours, until the acid has dissolved.

The aqueous solution is extracted with ether and then acidified withconcentrated hydrochloric acid with stirring. The precipitated productis collected, washed thoroughly with water and dried in a vacuum oven at50° C. over potassium hydroxide pellets to give3-fluoro-α-methyl-4-methoxycinnamic acid, m.p. 167°-169° C.; R_(f) 0.5on silica-gel G with methylene chloride-methanol (1:1).

(C) 3-fluoro-4-methoxy-α-methyl dihydrocinnamic acid

3-fluoro-4-methoxy-α-methylcinnamic acid, 49.5 g (0.236 mol) in 800 mlmethanol is hydrogenated at 43 lbs. pressure and room temperature untilthe theoretical uptake of hydrogen has occurred (24 min. at 20° C.,using 1.5 g platinum oxide catalyst). The solution is filtered and isevaporated with warming to 60° to give 3-fluoro-4-methoxy-α-methyldihydrocinnamic acid, R_(f) 0.5 on silica-gel G with methylenechloride-methanol (9:1).

(D) 5-fluoro-6-methoxy-2-methylindanone

A mixture of 3-fluoro-α-methyl-4-methoxy dihydrocinnamic acid, 49.3 g(0.23 mol) in 500 g of polyphosphoric acid is heated at 950 C. on asteam bath with occasional agitation for 75 min. The dark red solutionis poured into 3.0 l of water, and the mixture is stirred overnight. Theprecipitated product is collected, is washed thoroughly with water, andis taken up in ether. The ether solution is extracted with aqueouspotassium bicarbonate (4×), diluted with methylene chloride and dried(MgSO₄).

The organic solution is evaporated and recrystallized from methylenechloride petroleum ether to give 5-fluoro-6-methoxy-2-methylindanone,(m.p. 76°-78°).

(E) Methyl 6-fluoro-5-methoxy-2-methyl-3-indenyl-acetate

Into a 500 ml three-necked flask fitted with mechanical stirrer, refluxcondenser, drying tube, dropping funnel and nitrogen inlet is placed 6.0g zinc sheet and 100 ml of dry benzene. A few milliliters of a solutionof 21.3 g (0.11 mol) of 5-fluoro-6-methoxy-2-methylindanone and 18.36 g(0.121 mol) of methyl bromoacetate in 100 ml of dry benzene is added ata time. A crystal of iodine is added. The mixture is gently heated withstirring. After the iodine color has disappeared, the remainder of themixture is added gradually. The mixture is heated at reflux temperaturefor 18 h, and is then poured onto 600 ml of 5% H₂ SO₄ water and about500 g of ice. Some ether is added. The organic layer is separated and iswashed with three portions of 5% H₂ SO₄, KHCO₃ solution and finallywater. The organic layer is dried (MgSO₄) and is concentrated to give27.6 g of reddish oil which crystallizes slowly. Thin-layerchromatography on silica-gel G with methylene chloride methanol (99:1)shows product at R_(f) 0.5.

Without further purification, the hydroxy ester is dehydrated to theindenylacetate. In 200 ml of dry benzene, 14.2 g (53 mol) of crude esterand 36 g of phosphorus pentoxide are refluxed with stirring for 1/2hour. After cooling, the reaction mixture is filtered. The solid residueis triturated with benzene. The benzene filtrate is washed with twoportions of salt water, is dried (MgSO₄), and is concentrated, to give aslightly colored oil which rapidly crystallizes. The crude product isrecrystallized from methylene chloride-petroleum ether to givemethyl-6-fluoro-5-methoxy-2-methyl-3-indenyl-acetate (m.p. 61°-62°).

(F)6-fluoro-5-methoxy-2-methyl-1-(p-methylthiobenzylidene)-3-indenylaceticacid

To a solution of methyl-6-fluoro-5-methoxy-2-methyl-3-indenyl acetate,9.3 g (0.037 mol) and p-methylthiobenzaldehyde, 6.3 g (1.1 equivalent)is added 16 ml (2.0 equivalents) of 25% methanolic sodium methoxide. Themixture is stirred at reflux under nitrogen for 2 h. An equal volume ofwater is added dropwise and refluxing continues for 30 minutes. Thesolution is cooked, diluted with water and extracted with ether.Residual ether is blown off with nitrogen. The aqueous solution isacidified with 50% glacial acetic acid. The precipitated product iscollected and washed thoroughly with water. The crude produced isrecrystallized from methanol to give6-fluoro-5-methoxy-2-methyl-1-(p-methylthiobenzylidene)-2-indenylaceticacid, m.p. 172°-174°.

(G)6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinyl-benzylidene)-3-indenylaceticacid

A solution of sodium periodate, 4.28 g (20 mol) in 40 ml of water isadded dropwise to6-fluoro-5-methoxy-2-methyl-1-(p-methylthiobenzylidene)-3-indenylaceticacid, 3.70 g (10 mmol) in 300 ml methanol and enough acetone to causesolution. This solution is stirred overnight at room temperature andfiltered. The filtrate is evaporated at 30° to a small volume whichcauses the product to precipitate. The suspension is diluted withseveral volumes of water, and is cooled. Collected crystals are washedwith water and methanol-water (1:1). The product is dried in vacuo overpotassium hydroxide pellets and then in a vacuum oven at 70° C. Thecrude product is recrystallized from methylene chloride-petroleum etherto give6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinyl-benzylidene)-3-indenylaceticacid (m.p. 190°-193°). 6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid isprepared according to the procedure of Example 1, part G by the additionof 1.0 mol of m-chloroperbenzoic acid per mol of6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid in an acetone solution.

(H) rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-5-fluoro-6-methoxy-2-methyl-3-(p-methylsulfinylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1', 4'-olido)-3',4':1,2!-5-fluoro-6-methoxy-2-methyl-3-(p-methylsulfinylbenzylidene)-indanis obtained, if(Z)-5-methoxy-6-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylaceticacid from part (G) is reacted according to the procedure of Example 2and Example 4. C₂₁ H₁₇ FO₄ S:384.42.

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-methoxy, R₅ =5-fluoro,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, and R₁₂=methylsulfinyl.

EXAMPLE 21 rac-(E)-1-(2'-Buten-1', 4'-olido)-3',4':1,2!-5-fluoro-6-methoxy-2-methyl-3-(p-methylsulfonylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-5-fluoro-6-methoxy-2-methyl-3-(p-methysulfonylbenzylidene)-indanis obtained, if(Z)-5-methoxy-6-fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylaceticacid from Example 20 part (G) is reacted according to the Example 1 andExample 3. C₂₁ H₁₇ FO₅ S:400.42

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-methoxy, R₅ =5-fluoro,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, and R₁₂=methylsulfonyl.

EXAMPLE 22 rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-hydroxy-2-methyl-3-(p-methysulfinylbenzylidene)-indan (A)5-hydroxy-2-methyl-1-(p-methylthiobenzylidene)-3-indenyl acetic acid

The reaction of Example 18D is repeated except that the startingmaterials are methyl 5-hydroxy-2-methyl-3-indenylacetate andp-methylthiobenzaldehyde. Using the same reaction conditions andtechniques, 5-hydroxy-2-methyl-1-(p-methyithiobenzylidene)-3-indenylacetic acid is obtained.

(B) 5-hydroxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenyl aceticacid

Using the procedure of Example 1, part F,5-hydroxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenyl acetic acidobtained in part (A).

(C) rac-(E)-1-(2'-buten-1',4'-olido)-3',4':1,2!-6-hydroxy-2-methyl-3-(p-methylsulfinylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-hydroxy-2-methyl-3-(p-methylsulfinylbenzylidene)-indan isobtained, if5-hydroxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acidis reacted according to the procedure of Example 2 and Example 4. C₂₀H₁₆ O₄ S:352.40.

R₁ hydrogen, R₂ and R₃ form a double bond, R₄ =6-hydroxy, R₅ =hydrogen,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, and R₁₂=methylsulfinyl.

EXAMPLE 23 rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-hydroxy-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (A)5-hydroxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid.

5-hydroxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acidis obtained from5-hydroxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid(see Example 22, part B) using the procedure of Example 1, part H.

(B) rac-(E)-1-(2'-buten-1',4'-olido)-3',4':1,2!-6-hydroxy-2-methyl-3-(p-methylsulfinylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-hydroxy-2-methyl-3-(p-methylsulfonylbenzylidene)-indan isobtained, if the(Z)-5-hydroxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylaceticacid is reacted according to the procedure of Example 1 and Example 3.C₂₀ H₁₆ O₅ S:368.40.

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-hydroxy, R₅ =hydrogen,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, and R₁₂=methylsulfonyl.

EXAMPLE 24 rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-methoxy-2-methyl-3-benzylidene-indan (A)5-methoxy-2-methyl-1-benzylidene-3-indenylacetic acid.

5-methoxy-2-methyl-1-benzylidene-3-indenylacetic acid is obtained, ifmethyl-5-methoxy-2-methyl-3-indenylacetate (see Example 18, part C) isallowed to react with benzaldehyde according to the procedure of Example18, part D.

(B) rac-(E)-1-(2'-buten-1',4'-olido)-3',4':1,2!-6-methoxy-2-methyl-3-benzylidene-indan

If 5-methoxy-2-methyl-1-benzylidene-3-indenylacetic acid is allowed toreact according to the procedure of Example 1 and Example 3,rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-methoxy-2-methyl-3-benzylidene-indan is obtained. C₂₀ H₁₆O₃ mw. 304.34

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-methoxy, R₅ =hydrogen,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁=hydrogen, and R₁₂ =hydrogen.

EXAMPLE 25 rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-methoxy-2-methyl-3-(p-chlorobenzylidene)-indan (A)5-methoxy-2-methyl-1-(p-chlorobenzylidene)-3-indenylacetic acid

5-methoxy-2-methyl-1-(p-chlorobenzylidene)-3-indenylacetic acid isobtained, if methyl-5-methoxy-2-methyl-3-indenylacetate (see Example 18,part C) is reacted with p-chlorobenzaldehyde according to the procedureof Example 18, part D.

(B) rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-methoxy-2-methyl-3-(p-chlorobenzylidene)-indan

If 5-methoxy-2-methyl-1-(p-chlorobenzylidene)-3-indenylacetic acid isreacted according to the procedure of Example 1 and Example 3,rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-methoxy-2-methyl-3-(p-chlorobenzylidene)-indan is obtained.C₂₀ H₁₅ ClO₃ mw. 338.79

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-methoxy, R₅ =hydrogen,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁=hydrogen, and R₁₂ =chloro.

EXAMPLE 26 rac-(E)-1-(2'-Buten-1',4'-olido)3',4':1,2!-6-methoxy-2-methyl-3-(p-methylbenzylidene)-indan (A)5-methoxy-2-methyl-1-(p-methylbenzylidene)-3-indenylacetic acid

5-methoxy-2-methyl-1-(p-methylbenzylidene)-3-indenylacetic acid isobtained, if methyl-5-methoxy-2-methyl-3-indenylacetate (see Example 18,part C) is reacted with p-toluylaldehyde according to the procedure ofExample 18, part D.

(B) rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-methoxy-2-methyl-3-(p-methylbenzylidene)-indan

If 5-methoxy-2-methyl-1-(p-methylbenzylidene)-3-indenylacetic acid isreacted according to the procedure of Example 1 and Example 3,rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-methoxy-2-methyl-3-(p-methylbenzylidene)-indan is obtained.C₂₁ H₁₈ O₃ mw. 318.37

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-methoxy, R₅ =hydrogen,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ and R₁₁=hydrogen, and R₁₂ =methyl.

EXAMPLE 27 rac-(E)-1-(2'-buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-benzylidene-indan (A)(Z)-5-Fluoro-2-methyl-1-benzylidene-3-acetic acid

When 5-Fluoro-2-methylindene-3-acetic acid (see Example 1, part D) isallowed to react with benzaldehyde according to the procedure of Example1 (part E), (Z)-5-Fluoro-2-methyl-1-benzylidene-3-acetic acid isobtained. C₁₉ H₁₅ FO₂ :294.32; mp. 184 ° C.

(B) rac-(E)-1-(2'-buten-l1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-benzylidene-indan

When (Z)-5-Fluoro-2-methyl-1-benzylidene-3-acetic acid is allowed toreact according to the procedures of Example 2 and Example 4, oneobtains rac-(E)-1-(2'-buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-benzylidene-indan. C₁₉ H₁₃ FO₂ :292.30;mp. 111° C.

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ 6-fluoro, R₅ =hydrogen,R₆ and R₈ form a double bond, R₇ =methyl, R₉, R₁₀, R₁₁, and R₁₂=hydrogen.

EXAMPLE 28 rac-(E)-1-(2 '-buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(3,4,5-trimethoxybenzylidene)-indan (A)(Z)-5-Fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-acetic acid

When 5-Fluoro-2-methylindene-3-acetic acid (see Example 1, part D) isallowed to react with 3,4,5-trimethoxybenzaldehyde according to theprocedure of Example 1 (part E), one obtains(Z)-5-Fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-acetic acid. C₂₂H₂₁ FO₅ :384.40; mp. 168 ° C.

(B) rac-(E)-1-(2'-buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(3,4,5-trimethoxybenzylidene)-indan

When (Z)-5-Fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-acetic acidis allowed to react according to the procedures of Example 2 and Example4, one obtains rac-(E)-1-(2'-buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(3 ,4,5-trimethoxybenzylidene)-indan. C₂₂H₁₉ FO₅ :382.38; mp. 150° C.

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =6-fluoro, R₅ =hydrogen,R₆ and R₈ form a double bond, R₇ =methyl, R₉ =hydrogen, R₁₀ =3-methoxy ,R₁₁ =4-methoxy, and R₁₂ =5-methoxy.

EXAMPLE 29 rac-ribo-(E)-1-Triazolo- 2',3':1",3"!-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(methylsulfonylbenzylidene)-indan

A solution of rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (seeExample 3) (1.0 g, 2.69 mmol) in DMF (30ml) is combined with a mixtureof NaN₃ (0.4 g, 6.15 mmol) in DMF (30 ml) and glacial acetic acid (5ml). After 4 days at room temperature the reaction mixture is addeddropwise to stirred ice-water (800 ml). A white precipitate is filteredoff, is washed with water (200 ml), and is recrystallized from MeOH, togive white crystals of rac-ribo-(E)-1-Triazolo-2',3':1",3"!-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(methylsulfonylbenzylidene)-indan (0.93g, 2.25 mmol, 84%). C₂₀ H₁₆ FN₃ O₄ S:413.42; mp. 185° C.

R₁ =hydrogen, R₂ and R₃ form a triazole, R₄ =6-fluoro, R₅ =hydrogen, R₆and R₈ form a double bond, R₇ =methyl, R₉, R₁₀ and R₁₁ =hydrogen, andR₁₂ =methylsulfonyl.

EXAMPLE 30 rac-threo-(E)-1-N,N-Diethylamino-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p)-methylsulfonylbenzylidene)-indan

rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (seeExample 3) (1.0 g, 2.69 mmol) in DMSO (2 ml) reacts with HNEt,2 (2 ml)for 3 weeks at room temperature. The excess of HNEt₂ is removed invacuo, and the DMSO solution is added dropwise to stirred ice-water (200ml). A light yellow solid is filtered off, is washed with water (50 ml),and is purified by flash chromatography (CH₂ Cl₂) to giverac-threo-(E)-1-N,N-Diethylamino-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan.(0.23 g, 0.50 mmol, 19%). C₂₅ H₂₈ FNO₄ S:457.56; mp. 208° C.

R₁ =hydrogen, R₂ =hydrogen, R₃ =diethylamino, R₄ =6-fluoro, R₅=hydrogen, R₆ and R₈ form a double bond, R₇ =methyl, R₉, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 31 rac-threo-(E-)1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-1S-indanyl-mercaptoacetic acid

A mixture of rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (seeExample 3) (1.0 g, 2.69 mmol) and mercaptoacetic acid (0.21 ml, 3 mmol)in CH₃ CN (30 ml) / aq. 5% NaHCO₃ (20 ml) is stirred under N₂ for 24 h,at room temperature. The organic solvent is evaporated, and theremaining water phase is added slowly into stirred ice-HCl (200 ml,10%). The precipitate is filtered off, is washed with water (100 ml),and is recrystallized from CHCl₃ /n-hexane to give, as white crystalsrac-threo-(E)-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-1S-indanyl-mercaptoaceticacid (1.1 g, 2.38 mmol, 88%). C₂₂ H₁₉ FNO₆ S₂ :462.50; mp. 124° C.

R₁ =hydrogen, R₂ =hydrogen, R₃ =mercaptoacetic acid -H!, R₄ =6-fluoro,R₅ =hydrogen, R₆ and R₈ form a double bond, R₇ =methyl, R₉, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 32 rac-threo-(E-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl3-(p-methylsulfonylbenzylidene)-1S-indanyl-L-cysteine

A mixture of rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (seeExample 3) (15 g, 40.50 mmol) and L-cysteine (4.95 g, 40.85 mmol) in CH₃CN (450 ml) / H₂ O (75 ml) is stirred under N₂ for 10 d, at roomtemperature. The solvents are evaporated in vacuo. The residue isdissolved in hot MeOH (750 ml). Addition of water (1 L) leads to a whiteprecipitate, which is filtered off, and is washed with water (200 ml)and n-hexane (100 ml) to give rac-threo-(E)-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-1S-indanyl-L-cysteine.(18.3 g, 37.23 mmol, 91%). C₂₃ H₂₂ FNO₆ S₂ :491.54; mp. 160° C.

R₁ =hydrogen, R₂ =hydrogen, R₃ =cysteine -H!, R₄ =6-fluoro, R₅=hydrogen, R₆ and R₈ form a double bond, R₇ =methyl, R₉, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 33 rac-threo-(E)-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl -3-(p-methylsulfonylhenzylidene)-1S-indanyl-N-acetylcysteine

A mixture of rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (seeExample 3) (20 g, 54 mmol) in CH₃ CN (650 ml), with a solution ofN-Acetyl-L-cysteine (8.8 g, 53.92 mmol) / NaHCO₃ (6.6 g, 78.56 mmol) inwater (100 ml) is stirred under N₂ for 14 d, at room temperature. Thereaction mixture is concentrated (→150 ml) in vacuo and slowly added tocrushed ice/HCl (1 L, 10%). A white precipitate is filtered off, and iswashed with water (200 ml) and n-hexane (100 ml) to giverac-threo-(E)-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-1S-indanyl-N-acetylcysteine.(27.08 g, 50.75 mmol, 94%). C₂₅ H₂₄ FNO₇ S₂ :533.58; mp. 137° C.

R₁ =hydrogen, R₂ =hydrogen, R₃ =N--Ac-cysteine -H!, R₄ =6-fluoro, R₅=hydrogen, R₆ and R₈ form a double bond, R₇ =methyl, R₉, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 34 rac-threo-(E-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-1S-indanyl-glutathione

A suspension of rac-(E)-1-(2'-Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan (seeExample 3) (1.0 g, 2.69 mmol) and glutathione (0.92 g, 2.50 mmol) in CH₃CN / H₂ O (30 ml, 2:1) is stirred under N₂ for 7 d, at room temperature.The resulting solution is evaporated to dryness. The residue is driedazeotropically with toluene (3×20 ml). The excess of indane startingmaterial is extracted with boiling acetone. A white solid is filteredoff, is washed with acetone, and is dried, to giverac-threo-(E)-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-1S-indanyl-glutathione(1.68 g, 2.49 mmol, 98%). C₃₀ H₃₂ FNO₁₀ S₂ :677.73; mp. 150° C. (dec.).

R₁ =hydrogen, R₂ =hydrogen, R₃ =glutathione -H!, R₄ =6-fluoro, R₅=hydrogen, R₆ and R₈ form a double bond, R₇ =methyl, R₉, R₁₀ and R₁₁=hydrogen, and R₁₂ =methylsulfonyl.

EXAMPLE 35 rac-threo-3-(Butan-1',4'-olido)-3',4':3,2!-3-bromo-1-(4-chlorobenzoyl-5-methoxy-2-methyl-2,3-dihydroindole (A)2-methyl-5-methoxy-3-indolylacetic anhydride

Dicyclohexylcarbodiimide (10 g., 0.049 mole) is dissolved in a solutionof 2-methyl-5-methoxy-3-indolylacetic acid (22 g., 0.10 mole) in 200 ml.of THF, and the solution is allowed to stand at room temperature for 2hours. The precipitated urea is removed by filtration, and the filtrateis evaporated in vacuo to a residue and flushed with Skellysolve B. Theresidual oily anhydride is used without purification in the next step.

(B) t-Butyl 2-methyl-5-methoxy-3-indolylacetate

t-Butyl alcohol (25 ml.) and fused zinc chloride (0.3 g.) are added tothe anhydride from part A. The solution is refluxed for 16 hours andexcess alcohol is removed in vacuo. The residue is dissolved in ether,washed several times with saturated bicarbonate, water, and saturatedsalt solution. After drying over magnesium sulfate, the solution istreated with charcoal, evaporated, and flushed several times withSkellysolve B for complete removal of alcohol. The residual oily ester(18 g., 93%) is used without purification.

(C) t-Butyl 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolylacetate

A stirred solution of ester (18 g., 0.065 mole) in dry DMF (450 ml.) iscooled to 4° in an ice bath, and sodium hydride (4.9 g., 0.098 mole, 50%susp.) is added in portions. After 15 minutes, p-chlorobenzoyl chloride(15 g., 0.085 mole) is added dropwise during 10 minutes, and the mixtureis stirred for 9 hours without replenishing the ice bath. The mixture isthen poured into 1 l of 5% acetic acid, extracted with a mixture ofether and benzene, washed thoroughly with water, bicarbonate, saturatedsalt, dried over magnesium sulfate, treated with charcoal, andevaporated to a residue which partly crystallizes. This is shaken withether, filtered, and the filtrate is evaporated to a residue (17 g.)which solidifies after being refrigerated overnight. The crude productis boiled with 300 ml. of Skellysolve B, cooled to room temperature,decanted from some gummy material, treated with charcoal, concentratedto 100 ml., and allowed to crystallize. The product thus obtained (10g.) is recrystaaazed from 50 ml of methanol and gives 4.5 g. ofanalytically pure material, M.P. 103°-4°.

(D) 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolylacetic acid

A mixture of 1 g. ester and 0.1 g. powdered porous plate is heated in anoil bath at 210° with magnetic stirring under a blanket of nitrogen forabout 2 hours. No intensification of color (pale yellow) occurs duringthis period. After cooling under nitrogen, the product is dissolved inbenzene and ether, filtered, and extracted with bicarbonate. The aqueoussolution is filtered with suction to remove ether, neutralized withacetic acid, and then acidified weakly with dilute hydrochloric acid.The crude product (0.4 g., 47%) is recrystalized from aqueous ethanoland dried in vacuo at 65°; M.P. 151°.

(E) rac-threo-3-(Butan-1',4'-olido)-3',4':3,2!-3-bromo-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-2,3-dihydroindole

When 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid isallowed to react according to the procedure of Example 2, one obtainsrac-threo-3-(Butan-1',4'-olido)-3',4':3,2!-3-bromo-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-2,3-dihydroindole.(14.49 g, 33.20 mmol, 83%). C₁₉ H₁₅ BrClNO₄ :436.68; mp. 110° C. (dec.).

R₁ =hydrogen, R₂ =hydrogen, R₃ =bromo, R₅ =S-methoxy, R₅ =hydrogen, R⁶-X =nitrogen, R₈ --C--R₉ =carbonyl, R₇ =methyl, R₁₀ and R₁₁ =hydrogen,and R₁₂ =chloro.

EXAMPLE 36 rac-3-(2'-Buten-1',4'-olido)3',4':3,2!-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-2,3-dihydroindole

rac-threo-3-(Butan-1',4'-olido)-3',4':3,2!-3-bromo-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-2,3-dihydroindolefrom Example 35 reacts with N,N-diisopropylethylamine according to theprocedure of Example 4 to give rac-3-(2'-Buten-1',4'-olido)-3',4':3,2!-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-2,3-dihydroindole.(9.35 g, 26.28 mmol, 91%). C₉ H₁₄ ClNO₄ :355.77; mp. 169° C.

R₁ =hydrogen, R₂ and R₃ form a double bond, R₄ =5-methoxy, R₅ =hydrogen,R⁶ -X =nitrogen, R₈ --C--R₉ =carbonyl, R₇ =methyl, R₁₀ and R₁₁=hydrogen, and R₁₂ =chloro.

EXAMPLE 37 rac-threo-3-(Butan-1',4'-olido)-3',4':3,2!-3-(N,N'-diethylaminoethanethio)-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-2,3-dihydroindole

rac-3-(2'-Buten-1',4'-olido)-3',4':3,2!-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-2,3-dihydroindole fromExample 36 reacts with 2-diethylaminoethanethiol x HCl according to theprocedure of Example 12 to give rac-threo-3-(Butan-1',4'-olido)-3',4':3,2!-3-(N,N'-diethylaminoethanethio)-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-2,3-dihydroindole.C₂₅ H₂₉ ClN₂ O₄ :489.01; mp. 101° C.

R₁ =hydrogen, R₂ =hydrogen, R₃ =S--CH₂ CH₂ --N(Et)₂, R₄ =5-methoxy, R₅=hydrogen, R⁶ -X =nitrogen, R₈ --C--R₉ =carbonyl, R₇ =methyl, R₁₀ andR₁₁ =hydrogen, and R₁₂ =chloro.

Biological Effects

The compounds of this invention were assayed for their effect on variouscell lines representative of precancerous lesions to ascertain thedegree of tumor growth inhibition following treatment with compounds ofthis invention. The cell lines employed for these experiments were wellcharacterized, and are used by the United States National CancerInstitute in their screening program for new anti-cancer drugs. Growthinhibition of this cell line is thought to be indicative of a benefit onprecancerous lesions and neoplasms.

Tumor cell cytotoxicity was assessed using the Sulforhodamine B Assay.In this assay, tumor cells were plated in 96-well plates and treatedwith drug-containing media for seven days (continuous exposure). At theend of the exposure period, the cells were fixed and stained withsulforhodamine B (a pink fluorescent dye). The dye was then solubilized,and the optical density of the resulting pink solution determined on a96-well plate reader. The mean dye intensity of the treated wells wasthen divided by the mean dye intensity in the control wells (6 wells ofeach) to determine the effect of the drug on the cells. Dye intensity isproportional to the number of cells or amount of protein per well. Theresultant "percent of control" value then represents the degree ofgrowth inhibition caused by the drug.

For each experiment, an IC₅₀ value was determined and used forcomparative purposes. This value is equivalent to the concentration ofdrug needed to inhibit tumor cell growth by 50%. IC₅₀ values wereobtained graphically by connecting the mean values for each drugconcentration tested. Each experiment included at least six wells perdrug concentration. Concentration was plotted on a log scale on theX-axis. IC₅₀ values obtained for the compounds of Examples 1 and 3 areprovided in Table I below for several cell lines.

                  TABLE I                                                         ______________________________________                                                                I.C..sub.50                                                                              I.C..sub.50 Values                         Cell                    Values (μM)                                                                           (μM)                                    Line     Type           Example 1  Example 3                                  ______________________________________                                        HT-29    Human Colonic  0.48       0.28                                                Adenocarcinoma-                                                               moderately well defined                                              MCF7/S   Human Breast              0.20                                                Adenocarcinoma                                                       A427     Human Lung                0.31                                                Adenocarcinoma                                                       UACC375  Human Melanoma            0.35                                                Adenocarcinoma                                                       ______________________________________                                         IC.sub.50 values for other compounds of this invention for the HT29p136       cell line (a human colonic adenocarcinoma) are listed in Table II below. 

                  TABLE II                                                        ______________________________________                                        EXAMPLE    IC.sub.50 (μM)                                                                            CELL LINE                                           ______________________________________                                        2          0.081          HT-29 p 135                                         4          0.11           HT-29 p 135                                         5          0.31           HT-29 p 133                                         6          27.            HT-29 p 133                                         7          26.            HT-29 p 133                                         8          78.            HT-29 p 133                                         9          110.           HT-29 p 135                                         11         100.           HT-29 p 135                                         12         0.39           HT-29 p 133                                         13         >50.           HT-29 p 136 (?)                                     27         0.34           HT-29                                               28         0.28           HT-29                                               29         2.4            HT-29                                               30         0.35           HT-29                                               31         50             HT-29                                               32         2.1            HT-29                                               33         30             HT-29                                               34         3.6            HT-29                                               36         2              HT-29                                               37         29             HT-29                                               ______________________________________                                    

Compounds of this invention, as well as several others (see Table IIbelow), were evaluated to determine whether they inhibited theproduction of prostaglandin E₂ (PGE₂), according to the procedure below.Briefly, the procedure employs HL-60, human promyelocytes, which aredifferentiated with DMSO in mature granulocytes (Collins, S. J.,Ruscetti, F. W., Gallagher, R. E. and Gallo, R. C. (1979) Normalfunctional characteristics of cultured human promyelocytic leukemiacells (HL-60) after induction of differentiation by dimethylsulfoxide ,J. Exp. Med. 149:969-974). These differentiated cells produce PGE₂ afterstimulation with a calcium ionophore A23187 (Kargman, S., Prasit, P. andEvans, J. F. (1991) Translocation of HL-60 cell 5-lipoxygenase. J. Biol.Chem. 266: 23745-23752). Secreted PGF₂ is measured using an enzymeimmunoassay (EIA) kit.

Specifically, HL-60 is a human promyelocytic cell line which may bedifferentiated in mature granulocytes in the presence of compounds suchas dimethyl sulfoxide (DMSO). These cells are obtained from the AmericanType Culture Collection (ATCC:CCL240). They are grown in a RPM'1640medium supplemented with 20% heat-inactivated fetal bovine serum, 50U/ml penicillin and 50 μg/ml streptomycin in an atmosphere of 5% CO₂ at37° C. To induce myeloid differentiation, cells are exposed to 1.3% DMSOfor 9 days and then washed and resuspended in Dulbecco'sphosphate-buffered saline at 3×10⁶ cells/ml.

The differentiated HL-60 cells (3×10⁶ cells/ml) are incubated for 15 minat 37° C. in the presence of the compounds listed in Table II at thedesired concentration. Cells are then stimulated by A23187 (5×10⁻⁶ M)for 15 min. Secreted PGE₂ into the external medium is measured by EIAusing a commercially available EIA kit.

The quantity of PGE₂ secreted is expressed in ng/10⁶ cells using astandard curve. Data are converted using a curve fitting of the fourparameter logistic equation: ##EQU1## Results, expressed as the presentof control, are the mean ±s.e.m. of n=3 independent measurements. TheIC₅₀ values are determined using Hill equation. The effects of thetested compounds on PGE₂ production by human granulocytes are shown inTable III.

Indomethacin inhibits PGE₂ production with an IC₅₀ value of 2nM inaccordance with this standard. The sulfone inhibits PGE₂ production onlyat relatively high concentrations: the IC₅₀ value is 100μM. Thecompounds sulindac sulfide and Example 3 above, studied at 10-⁵ M,inhibit PGE₂ production by 100% and 79% respectively.

                  TABLE III                                                       ______________________________________                                                               (Anti-PG                                                                      Synthetase SELECTIVITY                                           (Anti-proliferative                                                                        activity)  INDEX                                                 activity)    PGE.sub.2 I.C..sub.50                                                                    (HT-29 IC.sub.50 /                          Drug      HT-29 I.C..sub.50 (μM)                                                                  (μM)    PGE.sub.2 IC.sub.50)                        ______________________________________                                        Sulfone   119          100        1.19                                        Sulindac  64           0.05       1,280                                       Sulfide                                                                       Indomethacin                                                                            66           0.002      33,000                                      Diclofenac                                                                              55           0.001      55,000                                      Salicylic Acid                                                                          2333         0.3        7,776                                       Ibuprofen 520          0.2        2,600                                       Example 3 0.28         40         0.007                                       Example 12                                                                              0.43         >100       <0.0043                                     Example 29                                                                              2.4          1.5        1.6                                         Example 30                                                                              0.35         >100       <0.0035                                     Example 34                                                                              3.6          >100       <0.036                                      Example 36                                                                              2            0.08       25                                          ______________________________________                                    

Given that high levels of anti-PG synthetase activity are associatedwith undesirable side-effects (e.g., gastric irritation and ulceration),the ratios of antiproliferative activity to anti-PG synthetase activity(i.e. the "selectivity index" referred to in Table II) is important.Lower selectivity indices provide greater opportunities foradministering therapeutic levels of compound while minimizing the riskof gastrointestinal side-effects. For example, the sulindac sulfide,which has good anti-proliferative activity (IC₅₀ =44μm), unfortunatelymanifests a high degree of anti-PG-synthetase activity which precludessafe, long-term treatment for pre-cancerous lesions. In marked contrast,the compounds of this invention (as exemplified by the compound ofExample 3 in Table II) has outstanding anti-proliferative activity whileessentially lacking anti-prostaglandin activity at therapeuticconcentrations. Compounds of this invention, therefore, are excellentcandidates for long term use as therapeutic agents for pre-cancerouslesions.

The compounds of this invention can be formulated with pharmaceuticallyacceptable carriers into unit dosage forms in a conventional manner sothat the patient in need of therapy for precancerous lesions canperiodically (e.g. once or more per day) take a compound according tothe method of this invention.

The exact initial dose of the compounds of this invention can bedetermined with reasonable experimentation, but is believed to bebetween 0.375 mg/day to 5 mg/day in the average adult.

It will be understood that various changes and modifications can be madein the details of procedure, formulation and use without departing fromthe spirit of the invention, especially as defmed in the followingclaims.

We claim:
 1. A compound comprising: ##STR3## wherein X is selected fromthe group consisting of carbon or nitrogen; when X is nitrogen, R⁶ isabsent;R₁ and R₂ are independently selected from the group consisting ofhydrogen, amino, lower alkyl, lower alkoxy, azide, hydroxy, halogen,acetoxyl, benzoxy, or substituted phenyl where the substituents areselected from the group consisting of halogen, lower alkyl, or loweralkoxy; or R₁ and R₂ form a carbonyl or imine; or R₂ and R₃ togetherform a double bond, aziridin, epoxide or triazole; or a dioxolane; R₃ isselected from the group consisting of hydrogen, halogen, azide, loweralkoxy, cyano, hydroxy, di(lower)alkyl amino(lower)alkylthio,loweralkylthio, phenylthio, or di(lower) alkylamino; or, R₃ is furtherselected from a group consisting of mercaptoacetic acid, cysteine,N-Ac-cysteine and glutathione; R₄ is selected from the group consistingof hydrogen, hydroxy, halogen, lower alkoxy or lower alkyl, or lowerdialkyl amino; R₅ is selected from the group consisting of hydrogen,hydroxy, halogen, lower alkoxy, lower alkyl, amino, or lower dialkylamino; R₆ is selected from the group consisting of hydrogen, loweralkyl, hydroxy, lower alkoxy, halogen or R₆ and R₈ together from adouble bond; R₇ is selected from the group consisting of hydrogen, loweralkyl, phenyl, halo(lower)alkyl, hydroxy(lower)alkyl,acetoxy(lower)alkyl, benzyloxy(lower)alkyl, or(lower)alkyl(lower)alkoxy, or di(lower)alkylamiino(lower)alkyl; R₈ andR₉ are independently selected from the group consisting of hydrogen,lower alkyl, hydroxy, lower alkoxy, or halogen; or R₉ and R₉ togethermay be oxygen; R₁₀ and R₁₁, are independently selected from the groupconsisting of hydrogen, halogen, lower alkoxy, or lower alkyl; and R₁₂is selected from the group consisting of hydrogen, halogen, lower alkyl,lower alkoxy, lowerkylthio, loweralkylsulfinyl, lower alkyl sulfonyl, oramidosulfonyl.
 2. The compound of claim 1 where X is nitrogen.
 3. Thecompound of claim 2 wherein R₁ and R₂ are independently selected fromthe group consisting of hydrogen, amino, lower alkyl, lower alkoxy,azide, hydroxy, or halogen, or R₁ and R₂ form a carbonyl; or R₂ and R₃form a double bond, aziridin, epoxide, triazole or dioxolane;R₄ and R₅are independently selected from the group consisting of hydrogen,halogen or lower alkoxy; R₇ is selected from the group consisting ofhydrogen, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,acetoxy(lower)alkyl, benzyloxy(lower)alkyl, or(lower)alkyl(lower)alkoxy; R₈ and R₉ together are an oxygen; and R₁₀-R₁₁ are hydrogen.
 4. The compound of claim 1 wherein X is carbon. 5.The compound of claim 4 wherein R₁ and R₂ are independently selectedfrom the group consisting of hydrogen, amino, lower alkyl, lower alkoxy,azide, hydroxy, or halogen, or R₁ and R₂ form a carbonyl; or R₂ and R₃form a double bond, aziridin, epoxide, triazole or dioxolane;R₄ and R₅are independently selected from the group consisting of hydrogen,halogen or lower alkoxy; R₆ is hydrogen or together with R₈ forms adouble bond; R₇ is selected from the group consisting of hydrogen, loweralkyl, halo(lower)alkyl, hydroxy(lower)alkyl, acetoxy(lower)alkyl,benzyloxy(lower)alkyl, or (lower)alkyl(lower)alkoxy; and R₈ -R₁₁ arehydrogen.
 6. The compound of claim 5 wherein R₄ and R₅ are independentlyselected from the group consisting of hydrogen and halogen.
 7. Thecompound of claim 6 wherein R₁₂ is lower alkyl sulfonyl.
 8. The compoundof claim 6 wherein R₄ is halogen and R₅ is hydrogen.
 9. The compound ofclaim 8 wherein R₇ is lower alkyl.
 10. The compound of claim 5 whereinthe compound is rac-(E)-1-Triozolo- 2',3':1,3"!-1-(butan-1',4'-olido)-3',4':1 ,2!-6-fluoro-2-methyl-3-(methylsulfonylbenzylidene)-indan. 11.The compound of claim 5 wherein the compound israc-(E)-1-(N,N'-diethylaminoethanethio)-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan. 12.The compound of claim 5 wherein the compound israc-(E)-1-bromo-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan. 13.A method of treating a patient having precancerous lesions in need oftreatment, comprising administering to the patient a physiologicallyeffective amount of a compound of the formula: ##STR4## wherein X isselected from the group consisting of carbon and nitrogen; when X isnitrogen R⁶ is absent;R₁ and R₂ are independently selected from thegroup consisting of hydrogen, amino, lower alkyl, lower alkoxy, azide,hydroxy, halogen, acetoxyl, benzoxy, or phenyl or substituted phenylwhere the substituents are selected from the group consisting ofhalogen, lower alkyl, or lower alkoxy; or R₁ and R₂ form a carbonyl orimine; or R₂ and R₃ together form a double bond, aziridin, epoxide ortriazole; or a dioxolane; R₃ is selected from the group consisting ofhydrogen, halogen, azide, lower alkyl, lower alkoxy, cyano, hydroxy,di(lower)alkyl amino(lower)alkylthio, loweralkylthio, phenylthio,di(lower) alkylamino, or from a group consisting of mercaptoacetic acidcysteine N--Ac-cysteine and glutathione; R₄ is selected from the groupconsisting of hydrogen, hydroxy, halogen, lower alkoxy or lower alkyl,or lower dialkyl amino; R₅ is selected from the group consisting ofhydrogen, hydroxy, halogen, lower alkoxy, lower alkyl, amino, or lowerdialkyl amino; R₆ is selected from the group consisting of hydrogen,lower alkyl, hydroxy, lower alkoxy, halogen or R₆ and R₈ together from adouble bond; R₇ is selected from the group consisting of hydrogen, loweralkyl, phenyl, halo(lower)alkyl, hydroxy(lower)alkyl,acetoxy(lower)alkyl, benzyloxy(lower)alkyl, or(lower)alkyl(lower)alkoxy, or di(lower)alkylamino(lower)alkyl; R₈ and R₉are independently selected from the group consisting of hydrogen, loweralkyl, hydroxy, lower alkoxy, or halogen; R₁₀ and R₁₁ are independentlyselected from the group consisting of hydrogen, halogen, lower alkoxy,or lower alkyl; and R₁₂ is selected from the group consisting ofhydrogen, halogen, lower alkyl, lower alkoxy, loweralkylthio,loweralkylsulfinyl, lower alkyl sulfonyl, or amidosulfonyl.
 14. Themethod of claim 13 wherein X is nitrogen.
 15. The method of claim 14wherein R₁ and R₂ are independently selected from the group consistingof hydrogen, amino, lower alkyl, lower alkoxy, azide, hydroxy, orhalogen, or R₁ and R₂ form a carbonyl; or R₂ and R₃ form a double bond,aziridin, epoxide, triazole or dioxolane;R₄ and R₅ are independentlyselected from the group consisting of hydrogen, halogen or lower alkoxy;R₇ is selected from the group consisting of hydrogen, lower alkyl,halo(lower)alkyl, hydroxy(lower)alkyl, acetoxy(lower)alkyl,benzyloxy(lower)alkyl, or (lower)alkyl(lower)alkoxy; R₈ and R₉ togetherare an oxygen; and R₁₀ and R₁₁ are hydrogen.
 16. The method of claim 13wherein X is carbon.
 17. The method of claim 16 wherein R₁ and R₂ areindependently selected from the group consisting of hydrogen, amino,lower alkyl, lower alkoxy, azide, hydroxy, or halogen, or R₁ and R₂ forma carbonyl; or R₂ and R₃ form a double bond, aziridin, epoxide, triazoleor dioxolane;R₄ and R₅ are independently selected from the groupconsisting of hydrogen, halogen or lower alkoxy; R₆ is hydrogen ortogether with R₈ forms a double bond; R₇ is selected from the groupconsisting of hydrogen, lower alkyl, halo(lower)alkyl,hydroxy(lower)alkyl, acetoxy(lower)alkyl, benzyloxy(lower)alkyl, or(lower)alkyl(lower)alkoxy; and R₈ -R₁, are hydrogen.
 18. The method ofclaim 17 wherein R₄ and R₅ are independently selected from the groupconsisting of hydrogen and halogen.
 19. The method of claim 18 whereinR₁₂ is lower alkyl sulfonyl.
 20. The method of claim 18 wherein R₄ ishalogen and R₅ is hydrogen.
 21. The method of claim 20 wherein R₇ islower alkyl.
 22. The method of claim 16 wherein said compound israc-ribo-(E)-1-triazolo-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(methylsulfonylbenzylidene)-indan. 23.The method of claim 16 wherein said compound israc-(E)-1-(N,N'-diethylaminoethanethio)-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan. 24.A method for inhibiting the growth of neoplastic cells comprisingexposing said cells to an effective amount of a compound of the formula:##STR5## X is selected from the group consisting of carbon and nitrogen;when X is nitrogen R⁶ is absent;R₁ and R₂ are independently selectedfrom the group consisting of hydrogen, amino, lower alkyl, lower alkoxy,azide, hydroxy, halogen, acetoxyl, benzoxy, or phenyl or substitutedphenyl where the substituents are selected from the group consisting ofhalogen, lower alkyl, or lower alkoxy; or R₁ and R₂ from a carbonyl orimine; or R₂ and R₃ together form a double bond, aziridin, epoxide ortriazole; or a dioxolane; R₃ is selected from the group consisting ofhydrogen, halogen, azide, lower alkyl, lower alkoxy, cyano, hydroxy,di(lower)alkyl amino(lower)alkylthio, loweralkylthio, phenylthio,di(lower)alkylamino, or from a group consisting of mercaptoacetic acid,cysteine, N--Ac-cysteine and glutathione; R₄ is selected from the groupconsisting of hydrogen, hydroxy, halogen, lower alkoxy or lower alkyl,or lower dialkyl amino; R₅ is selected from the group consisting ofhydrogen, hydroxy, halogen, lower alkoxy, lower alkyl, amino, or lowerdialkyl amino; R₆ is selected from the group consisting of hydrogen,lower alkyl, hydroxy, lower alkoxy, halogen or R₆ and R₈ together from adouble bond; R₇ is selected from the group consisting of hydrogen, loweralkyl, phenyl, halo(lower)alkyl, hydroxy(lower)alkyl,acetoxy(lower)alkyl, benzyloxy(lower)alkyl, or(lower)alkyl(lower)alkoxy, or di(lower)alkylamino(lower)alkyl; R₈ and R₉are independently selected from the group consisting of hydrogen, loweralkyl, hydroxy, lower alkoxy, or halogen; or R₈ and R₉ together may beoxygen; R₁₀ and R₁₁ are independently selected from the group consistingof hydrogen, halogen, lower alkoxy, or lower alkyl; and R₁₂ is selectedfrom the group consisting of hydrogen, halogen, lower alkyl, loweralkoxy, loweralkylthio, loweralkylsulfinyl, lower alkyl sulfonyl, oramidosulfonyl.
 25. The method of claim 24 wherein X is nitrogen.
 26. Themethod of claim 25 wherein R₁ and R₂ are independently selected from thegroup consisting of hydrogen, amino, lower alkyl, lower alkoxy, azide,hydroxy, or halogen, or R₁ and R₂ form a carbonyl; or R₂ and R₃ form adouble bond, aziridin, epoxide, triazole or dioxolane;R₄ and R₅ areindependently selected from the group consisting of hydrogen, halogen orlower alkoxy; R₇ is selected from the group consisting of hydrogen,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, acetoxy(lower)alkyl,benzyloxy(lower)alkyl, or (lower)alkyl(lower)alkoxy; R₈ -R₉ together arean oxygen; and R₁₀ -R₁₁ are hydrogen.
 27. The method of claim 26 whereinR₁ is an oxygen and R₇ is selected from the group consisting of hydrogenand lower alkyl.
 28. The method of claim 24 wherein X is carbon.
 29. Themethod of claim 28 wherein R₁ and R₂ are independently selected from thegroup consisting of hydrogen, amino, lower alkyl, lower alkoxy, azide,hydroxy, or halogen, or R₁ and R₂ form a carbonyl; or R₂ and R₃ form adouble bond, aziridin, epoxide, triazole or dioxolane;R₄ and R₅ areindependently selected from the group consisting of hydrogen, halogen orlower alkoxy; R₆ is hydrogen or together with R₈ forms a double bond; R₇is selected from the group consisting of hydrogen, lower alkyl,halo(lower)alkyl, hydroxy(lower)alkyl, acetoxy(lower)alkyl,benzyloxy(lower)alkyl, or (lower)alkyl(lower)alkoxy; and R₈ -R₁₁ arehydrogen.
 30. The method of claim 29 wherein R₁₂ is lower alkylsulfonyl.
 31. A pharmaceutical composition comprising an acceptablepharmaceutical carrier and a compound having the formula below: ##STR6##wherein X is selected from the group consisting of carbon or nitrogen;when X is nitrogen, R⁶ is absent;R₁ and R₂ are independently selectedfrom the group consisting of hydrogen, amino, lower alkyl, lower alkoxy,azide, hydroxy, halogen, acetoxyl, benzoxy, or substituted phenyl wherethe substituents are selected from the group consisting of halogen,lower alkyl, or lower alkoxy; or R₁ and R₂ form a carbonyl or imine; orR₂ and R₃ together form a double bond, aziridin, epoxide or triazole; ora dioxolane; R₃ is selected from the group consisting of hydrogen,halogen, azide, lower alkyl, lower alkoxy, cyano, hydroxy,di(lower)alkyl amino(lower)alkylthio, loweralkylthio, phenylthio, ordi(lower) alkylamino; or, R₃ is further selected from a group consistingof mercaptoacetic acid, cysteine, N--Ac-cysteine and glutathione; R₄ isselected from the group consisting of hydrogen, hydroxy, halogen, loweralkoxy or lower alkyl, or lower dialkyl amino; R₅ is selected from thegroup consisting of hydrogen, hydroxy, halogen, lower alkoxy, loweralkyl, amino, or lower dialkyl amino; R₆ is selected from the groupconsisting of hydrogen, lower alky, hydroxy, lower alkoxy, halogen or R₆and R₈ together from a double bond; R₇ is selected from the groupconsisting of hydrogen, lower alkyl, phenyl, halo(lower)alkyl,hydroxy(lower)alkyl, acetoxy(lower)alkyl, benzyloxy(lower)alkyl, or(lower)alkyl(lower)alkoxy, or di(lower)alkylamino(lower)alkyl; R₈ and R₉are independently selected from the group consisting of hydrogen, loweralkyl, hydroxy, lower alkoxy, or halogen; or R₈ and R₉ together may beoxygen; R₁₀ and R₁₁ are independently selected from the group consistingof hydrogen, halogen, lower alkoxy, or lower alkyl; and R₁₂ is selectedfrom the group consisting of hydrogen, halogen, lower alkyl, loweralkoxy, lowerkylthio, loweralkylsulfinyl, lower alkyl sulfonyl, oramidosulfonyl.
 32. The pharmaceutical composition of claim 31 where X isnitrogen.
 33. The pharmaceutical composition of claim 32 wherein R₁ andR₂ are independently selected from the group consisting of hydrogen,amino, lower alkyl, lower alkoxy, azide, hydroxy, or halogen, or R₁ andR₂ form a carbonyl; or R₂ and R₃ form a double bond, aziridin, epoxide,triazole or dioxolane;R₄ and R₅ are independently selected from thegroup consisting of hydrogen, halogen or lower alkoxy; R₇ is selectedfrom the group consisting of hydrogen, lower alkyl, halo(lower)alkyl,hydroxy(lower)alkyl, acetoxy(lower)alkyl, benzyloxy(lower)alkyl, or(lower)alkyl(lower)alkoxy; R₈ and R₉ together are an oxygen; and R₁₀-R₁₁ are hydrogen.
 34. The pharmaceutical composition of claim 30wherein X is carbon.
 35. The pharmaceutical composition of claim 34wherein R₁ and R₂ are independently selected from the group consistingof hydrogen, amino, lower alkyl, lower alkoxy, azide, hydroxy, orhalogen, or R₁ and R₂ form a carbonyl; or R₂ and R₃ form a double bond,aziridin, epoxide, triazole or dioxolane;R₄ and R₅ are independentlyselected from the group consisting of hydrogen, halogen or lower alkoxy;R₆ is hydrogen or together with R₈ forms a double bond; R₇ is selectedfrom the group consisting of hydrogen, lower alkyl, halo(lower)alkyl,hydroxy(lower)alkyl, acetoxy(lower)alkyl, benzyloxy(lower)alkyl, or(lower)alkyl(lower)alkoxy; and R₈ -R₁₁ are hydrogen.
 36. Thepharmaceutical composition of claim 35 wherein R₄ and R₅ areindependently selected from the group consisting of hydrogen andhalogen.
 37. The pharmaceutical composition of claim 36 wherein R₁₂ islower alkyl sulfonyl.
 38. The pharmaceutical composition of claim 36wherein R₄ is halogen and R₅ is hydrogen.
 39. The pharmaceuticalcomposition of claim 38 wherein R₇ is lower alkyl.
 40. Thepharmaceutical composition of claim 34 wherein the compound israc-(E)-1-(Buten-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan. 41.The pharmaceutical composition of claim 34 wherein the compound israc-(E)-1-Triozolo- 2',3':1",3"!-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(methylsulfonylbenzylidene)-indan. 42.The pharmaceutical composition of claim 34 wherein the compound israc-(E)-1-(N,N'-diethylaminoethanethio)-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3 -(p-methylsulfonylbenzylidene)-indan. 43.The pharmaceutical composition of claim 34 wherein the compound israc-(E)-1-bromo-1-(butan-1',4'-olido)-3',4':1,2!-6-fluoro-2-methyl-3-(p-methylsulfonylbenzylidene)-indan.